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Final Exams Spring 2020 > Med Chem Final Exam Deck > Flashcards

Med Chem Final Exam Deck Flashcards

1
Q

The Kefauver-Harris Amendments mandate…

A

efficacy as well as safety must be established before a drug can be marketed

and required the FDA to assess the efficacy of all drugs introduced since 1938.

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2
Q

Identify the drug shown in the picture.

A

Lansoprazole (Prevacid) – PPI

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3
Q

Give examples of noncyclic SNRIs

A

Venlafaxine

Duloxetine

Milnacipran

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4
Q

Avagacestat is what type of drug

A

Gamma-secretase inhibitor

it is not selective for APP (amyloid precursor protein) and has other substrates

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5
Q

Drugs that are directed against tumor DNA have 3 different MOAs. List them and give an example.

A
  • break the helix itself (cross-linkers)
  • interfere with DNA-related proteins (topoisomerase inhibitors)
  • modify the expression of genes (alkylating and methylating agents)
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6
Q

Identify the class of drug depicted in the photo.

Bonus: name each drug.

A

First generation beta blockers (non-selective)

Propranolol, Pindolol, Timolol

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7
Q

what are the two main considerations when making a prodrug?

A

effective conversion to active drug in the blood stream

the prodrug “shield” group is not toxic when released

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8
Q

What must all intercalators have in their structure?

A

Need large (usually multiple rings) planar (flat) surfaces so they can fit between pairs of DNA

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9
Q

What change occurs once a local anesthetic travels from the ECF to the ICF?

A

Because local anesthetics are basic aminds at pH 7.4, once they travel inside the cell into the more acidic environment, they become protonated

  • once it’s protonated, it can bind to a sodium channel and prevent influx
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10
Q

NMR stands for

A

nuclear magnetic resonance

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11
Q

What drug is used to treat hypothyroidism?

A

Levothyroxine - synthetic T4 (thyroxine)

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12
Q

True or false: branched chain groups are more lipophilic than straight chain groups.

A

False - branched chain groups are less lipophilic than straight chain groups.

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13
Q

phenotypic screening is a whole organism (or cell) approach that speeds up ______________.

A

physicochemical property optimization

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14
Q

Define medicinal chemistry.

A

the science that deals with the discovery/design of new therapeutic agents and their development into useful medicines.

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15
Q

What structural modifications can be made to increase BBB penetration?

A
  • reduce Pgp efflux
  • reduce hydrogen bond donors
  • increase lipophilicity
  • reduce molecular weight
  • replace carboxylic acid groups
  • add conformational rigidity
  • try to hitch a ride on uptake transporters
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16
Q

List and describe some of the methods that are available for target validation.

A
  • Check peer reviewed papers
  • Modern techniques allow us to check things in the lab in more efficient ways
  • Gene Knockout (removal of the gene that encodes for the biomolecule of interest - does it result in death of the pathogen, would inhibiting have same effect?)

RNAi - dsRNA interfering with expression of genes with sequences complementary to it (results in reduction of production of protein)

Small Molecule Probe

Animal Models

Computation Docking

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17
Q

describe the function of ester prodrugs

A

carboxylic acids are excellent HBA and HBD, but they ionize too easily which can be a problem in crossing membranes a prodrug is used to protect the acid function by making it an ester. the less polar ester can cross the membrane and be hydrolyzed to the acid by an esterase enzyme

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18
Q

Which alkylating agent’s toxicity can be treated using an adjunct therapy of mesna?

A

Cyclophosphamide. It’s main toxicity comes from acrolein and CAA.
Acrolein can be counted with mesna because mesna (injected in the active form and selectively reduced in the kidney) will concentrate in the bladder and scavenge acrolein.

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19
Q

What is the actual alkylating agent made from the prodrug ifosfamide?

A

Aziridine

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20
Q

What is the MOA of SGLT2 inhibitors?

A

SGLT2 (sodium glucose co-transporter 2) normally facilitates glucose reabsorption in the kidney
–so, SGLT2 inhibitors block the reabsorption of glucose in the kidney, thus increasing excretion and lowering blood glucose levels.

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21
Q

Identify the class of drug depicted in the photo

What is it indicated for?

Bonus: identify the drug.

A

H2 receptor antagonist (competitive inhibitor of histamine H2 receptors)

Short-term treatment of active duodenal ulcer, treatment of GERD

Pepside (Famotidine)

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22
Q

What type of drug is buproprion?

A
  • selective inhibitor of DA reuptake at the DA presynaptic neuronal membrane and an NRI (induces the release of both DA and NE)
  • also a selective inhibitor of neuronal nAChRs (gives it the ability to help reduce withdrawal symptoms following smoking cessation)
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23
Q

describe theranostics

A

the combination of diagnostics and therapeutics using the same molecular scaffold

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24
Q

To which class of drug do ranitidine (Zantac) and famotidine (pepside) belong?

A

H2-receptor antagonist.

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25
Q

Identify the drug in the picture. What class does it belong to?

Describe its MOA.

A

Pantoprazole (Protonix) – Proton Pump Inhibitor

  • inhibits the final step in gastric acid production (in the gastric parietal cell of the stomach)
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26
Q

What was the Food, Drug, and Cosmetic Act (FD and C Act) of 1938 signed in response to? What did it mandate?

A

Death of over 100 people, many of whom were children, due to the addition of diethylene glycol (antifreeze) in a marketed form of sulfanilamide.

It established that manufacturers must prove the safety of their products prior to marketing.

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27
Q

Why don’t peptides usually make good drug candidates?

A
  • rapidly proteolyzed in GIT and serum
  • poorly bioavailable
  • rapidly excreted
  • bind to multiple receptors
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28
Q

Why are menotropins used to induce ovulation?

A

Menotropins are prepared from the urine of post-menopausal women. hCG is naturally occurring in post-menopausal women, and hCG induces ovulation.

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29
Q

What criteria is in place when making a lead from a hit molecule?

A
  • potency must be in the nanomoles (100nM); - must have some bioavailability (>10%) - must not bind too much to proteins (<99.5%) - solubility (>10ug/mL) - C log P < 3 (not too lipophilic) - log D < 3 - molecular weight < 450 - P450 IC50 > 10 uM for the 5 major isozymes (cannot be lower because then it potently inhibits CYP450) - HERG screening (look for toxicity)
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30
Q

Define ED50, TD50, and LD50.

A

ED50- dose at which 50% of subjects exhibit a therapeutic response to a drug.

TD50 - dose at which 50% of subjects experience a toxic response

LD50 - dose at which 50% of subjects die

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31
Q

How are metaglinides different from sulfonylureas?

A

Metaglinides have a weaker binding affinity and faster dissociation from the SUR1 binding site that results in a much shorter duration of action

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32
Q

___________ provides a link between the genetic alterations and a disease phenotype.

What is identified when using this method? What are the downsides?

A

Phenotypic screening

Genes (and thus proteins) identified this way are more likely to cause the disease, rather than be a consequence of the disease

The downside is that we don’t know the MoA of the drug; it’s typically a way to discover the first compound and cost of a drug (like the first antibiotic)

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33
Q

What is the single most important factor in the approval or disapproval for a new drug?

A

Safety and effectiveness studies done in clinical trials - particularly the safety aspect

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34
Q

What is pitocin used for?

A

It’s indicated for initiation or improvement of uterine contractions, as well in controlling postpartum bleeding

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35
Q

What suffix is associated with DPP-4 inhibitors?

Give at least 1 example of a DPP-4 inhibitor drug.

A

—Gliptin

Sitagliptin
Vildagliptin

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36
Q

The use of a _________ is common in scientific presentations as the conclusion of a SAR study.

A

Molecular Activity Map

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37
Q

To make a biosimilar of a biologic, you must have:

A
  • proof of quality and similarity
  • PK bioequivalence
  • clinical safety and efficacy data
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38
Q

Which kind of topoisomerase inhibitor is able to bind to either the topo-DNA complex or the topoisomerase itself?

A

Topoisomerase 2 inhibitors

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39
Q

_____ can be differentiated into neurons (or other cell types) that harbor the same genetic mutation as the patient

A

iPSCs

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40
Q

What is the purpose of the two tri-fluoro methyl groups in NK1 antagonists?

A

Enhance the activity and improves the metabolism

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41
Q

what is a prodrug?

A

an inactive compound that is converted (either chemically or enzymatically) to the active form (once in the body)

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42
Q

Identify the class of the drug depicted in the photo.

What is it indicated for?

Bonus: name the drug.

A

Proton Pump Inhibitor.

Treatment in adults of duodenal ulcer and gastric ulcer, treatment of adults and children with GERD, and maintenance of healing of erosive esophagitis

Omeprazole (Prilosec)

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43
Q

What is the pharmacophore of morphines?

Describe the SAR of mu-opioid ligands.

A

Pharmacophore: 4-phenylpiperidine moiety SAR:

  • pKa of the N is 8.0-10.0; the protonated form is required
  • phenolic OH is mostly unionized and participates as H+ donor
    • is REQUIRED (an OR group works too)
  • activity will increase if E ring is eliminated
  • only tertiary amines provide clinically significant activity
  • agonists - R1 is methyl group or longer than 3 C
  • 7,8 double bond is responsible for action
  • 6alpha-OH is responsible for mast cell degranulation
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44
Q

How do anthracyclines cause cardiotoxicity? How can it be mitigated?

A

They form superoxide radicals and hydroxide radicals.
The hydroxide radicals are formed through the Fenton reaction, and cardiac tissues don’t have enough catalases or cytoprotective enzymes.
The solution is to co-administer an antioxidant and an iron chelator.

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45
Q

Define bioisostere.

A

Substituents or functional groups that have similar chemical and/or physical properties and which produce broadly similar biological properties.

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46
Q

Sulphonamide formation involves ___________.

A

combination of a secondary amine and sulphanyl chloride

the nitrogen is still connected to the original 2 R groups, but the hydrogen from the scondary amine is replaced with the sulphonyl group (s double bonded to 2 O’s (each with a double bond) and another R group)

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47
Q

when is the overall benefit-risk relationship of the drug evaluated during clinical studies?

A

Phase 3

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48
Q

Define the function of DPP-4.

A

DPP-4 inhibitors block dipeptidyl peptidase 4 (DPP-4), thus blocking the inactivation of incretins.

  • the incretin is then able to stimulate the increase of insulin secretion and inhibit the release of glucagon
  • -> this lowers blood glucose
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49
Q

Explain the process of SPOS (solid-phase organic synthesis)

A

It is provided by a solid support known as beads (or resins), thereby rendering the reactions heterogenous and conferring a simpler workup and purification

  • the resin is cross-linked polystyrene
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50
Q

What are the important points to remember about platinum compounds?

A
  • Platinum is electron deficient
  • must be stabilized by amino acids to prevent it from reacting with everything
  • NH3 act as stabilizing groups and chloride ions make for good leaving groups
  • when it cross-links the DNA in the cis configuration it cannot be repaired by the cells
  • side effects include nephrotoxicity, emetogenesis, and neurotoxicity (limiting factor in use)
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51
Q

Explain the biological basis of depression.

A

The levels of 3 different small molecules are involved:

1 - serotonin: anxiety, panic, phobia, and obsessive-compulsion

2 - dopamine: cognitive slowing, hypersomnia, anhedonia

3 - norepinephrine/noradrenaline: decreased concentration, decreased working memory, decreased information processing, fatigue

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52
Q

Define priviledged structures.

A

Certain scaffolds are capable of binding to multiple receptor targets.

  • the core scaffolds (molecular master keys) are viable starting poitns in library generation
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53
Q

The common site of attack for DNA cross linking is

A

the 7-position N of guanine

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54
Q

Describe the SAR of flexible opioids (anilidopiperidines like fentanyl)

A
  • no phenolic OH group
  • highly lipophilic, so rapidly crosses the BBB; fast and potent
  • SAR on R1 (nitrogen) = arylalkyl - high lipophilicity
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55
Q

What provides the framework for how to conduct well-controlled studies?

A

Good Laboratory Practices

  • assures quality and integrity of data
  • provides overall accountability
  • facilitates study reconstruction
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56
Q

what is chemical biology (chemical genetics)

A

using a chemical to probe to learn about biological functions (usually a signaling pathway)

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57
Q

What class of drug is depicted in the photo?

Bonus: identify each drug.

A

NRIs (norepinephrine reuptake inhibitors)

Left to right: protriptyline, nortriptyline, desipramine, maprotiline

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58
Q

How is rapid acting insulin different than regular insulin therapy?

A

Rapid acting insulin has had its amino acid sequence modified, allowing for the rapid action.

When insulin is dimerized or hexamerized, it is not active. The monomeric formation is the active formation.

Rapid acting insulin works because it has been modified to decrease the formation of dimers and hexamers, allowing it to absorb more quickly.

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59
Q

What is the MOA of prolia?

A

It is a RANKL receptor inhibitor
– binds to the receptor to inhibit osteoclast activation and formation

–> this is because when RANKL binds to its receptor on the surface of osteoclasts and osteoclast precursors, it stimulates formation and activation

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60
Q

What effect does conformational regidity have on potency of CNS agents?

A

Increased rigidity (rings) locks the molecule into the bioactive conformation and increases potency

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61
Q

What are some particular things to watch out for with monoamine oxidase inhibitors?

A
  • rarely first choice; mostly used in atypical depression and bulemia (off-label)
  • common side effects: insomnia, agitation, dizziness, dry mouth, headache, confusion

- certain foods will cause hypertensive crisis because of the release and potentiation of catecholamines (no milk!)

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62
Q

Identify the drug class shown in the picture.

List the specific drugs left to right (if you can)

A

Tricyclic SNRIs

Impiramine

Amitriptyline

Chlomipramine

Trimipramine

Doxepin

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63
Q

HGH is used to treat…

What is the MOA?

A

short stature of unknown cause

MOA - mimics natural growth hormone to stimulate growth and cellular reproduction

Examples: genotropin, norditropin, humatrope

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64
Q

a vast majority of imaging agents have a _______ that acts as a delivery vehicle to deliver the _______ to the site of action you want to image

A

organic scaffold

inorganic element

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65
Q

The average time it takes to bring a drug to market is

A

12-15 years

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66
Q

iPSC stands for

A

induced pluripotent stem cells

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67
Q

The active site of renin contains…

A

two aspartyl residues

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68
Q

Why were noncyclic SNRIs developed? How do they compare?

A

To remove unwanted adverse effects of tricyclic inhibitors

They are as efficacious as tricyclic inhibitors and produce a faster and greater antidepressant response than an SSRI alone

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69
Q

What is the MOA of statins?

A

Competititive inhibitor of HMGR

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70
Q

What is ovidrel and what is it used for?

A

recombinant hCG

induces ovulation by stimulating late phase follicular maturation and resumption of oocyte meiosis

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71
Q

How is Forteo able to work as a bone forming agent?

A

It increases the number of osteoblasts

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72
Q

Why is salmon the preferable source of calcitonin?

A

It has greater receptor affinity and a longer half-life than human calcitonin.

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73
Q

What is the MOA of sulfonylureas?

A

Bind to and close ATP sensitive K channels on the cell membrane of pancreatic beta cells
- this impacts the cell membrane structure and increases insulin secretion

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74
Q

Which stage of the cell cycle are anthracyclines specific to?

A

G2

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75
Q

Identify some drugs that function as cholinesterase inhibitors. What effect do they have when treating Alzheimer’s?

A

Donepezil, Rivastigmine, Galantamine

improves attention, thinking memory, language comprehension, and communication

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76
Q

Describe the SAR of local anesthetics.

A
  • lipophilic portion is essential for activity
  • lipid solubility increases with extent of substitution (# of carbons) on the aromatic ring and/or amino group (ex. tetracaine is more lipid soluble and thus has a higher potency than procaine; it also has way more carbons attached off the aromatic ring)
  • the lower the pKa, the more rapid onset of action (more uncharged form, faster diffusion inside the cell)
  • the clinically relevant pKa is 7.0-9.0
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77
Q

What treatment strategies are used for Parkinson’s Disease?

A
  • increase synthesis of DA in the brain (L-dopa)
  • activate DA receptors (D2 agonists)
  • decrease reuptake of DA at presynaptic space (MAO inhibitors)
  • decrease metabolism of DA (or its precursor L-dopa)
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78
Q

_________ was the first non-platinum based chemotherapeutic approved since the approval of platinum

A

velcade

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79
Q

Identify the class of drug depicted in the photo.

What is it indicated for?

Bonus: Which drug is it?

A

5-HT3 Antagonist

Indicated for prevention of nausea and/or vomiting.

KYTRIL (Granisetron)

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80
Q

Why can statins be considered transition state analogues?

A

They imitate the transition state of the first step of the reaction mechanism of HMG-CoA reductase

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81
Q

Define biomarker.

A

A biomarker is a marker of biological or physiological states that can be easily measured (ideally on a scale allowing determination of effective treatment)

Ex. Lactic acid buildup during exercise; WBC levels in HIV; etc

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82
Q

Which clinical phase takes the longest?

A

Phase 3 (2-6 years)

Phase 4 is continuous

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83
Q

Identify the type of drug shown in the photo. How does it compare to an SSRI?

A

Non-tricyclic secondary amine NRIs (nisoxetine)

  • the bulky 2-OMe group restricts the conformation of the phenyl ring, which aligns the HBA (methoxy) with the HBD of the binding site on the NET
  • The SERT binding site does not have the same alignment, so the methoxy group in the meta position is what gives the non-tricyclic NRIs their selectivity for NET!
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84
Q

Which drug is shown in the picture?

A

Omeprazole (Prilosec) - PPI

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85
Q

What is the MOA of BACE1?

A

Beta-secretase inhibitor

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86
Q

What is unique about the MOA of PPIs?

A

They’re one of the only drug classes that actually form covalent bonds with their target receptors

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87
Q

what is evaluated in non-clinical drug development?

A

toxicity and efficacy through in vitro and in vivo lab animal testing

  • toxicology (acute, sub-chronic, chronic, genotoxicity (mutagenicity), and teratogenicity) - also dose escalation
  • pharmacology (ADME profile)
88
Q

What is the MOA of thiazolidinediones (glitazones)?

A

Binds to PPAR (peroxisome proliferator-activated receptor) gamma in adipocytes to promote adipogenesis and fatty acid uptake
- this decreases the amount of fatty acids present in circulation so that cells use more glucose

89
Q

Identify the major stages of drug development.

A

Target identification - determine the target that is important to heal the process/treat the disease

Target validation - prove the target (when affected) improves the disease outcome

Target to hit - identify the molecule with activity at the target

Hit to lead - determine the most potent hit molecule

Lead Optimization - how do we administer the drug? and other PK questions

Preclinical - lab and animal studies

Clinical Studies (phases 1-3)

90
Q

How does follistim work?

A

It stimulates ovarian follicular growth because it is made to resemble FSH

(FSH is the hormone produced in the anterior pituitary to normally stimulate follicular growth, maturation, and gonadal steroid production)

91
Q

What are the goals when conducting structural modifications?

A
  • increasing potency or selectivity
  • increasing the therapeutic index (a measure of the ratio of the concentration of a drug that gives undesirable effects to that which gives desirable effects)
  • we want a large LD50 and small ED50
92
Q

To which drug class does metoclopramide (reglan) belong?

A

Prokinetic agent (motility stimulant)

93
Q

Describe the drug repurposing strategy.

A

It seeks new medical treatments from among existing licensed medications rather than development of new molecules.

Advantages: available PK, PD, and posology data; knowledge of safety, toxicity, and rare adverse events; clinical experience is derived from original indications; widespread availability; low cost; undering the MOA and/or molecular targets

94
Q

The 1902 Biologics Control Act was enacted in response to…

A

13 children died from Jim the horse who had contracted tetanus (and whose tainted blood was used to treat patients)

95
Q

For the SAR of antimicrobial drugs, what is required for antimicrobial activity?

A

Groups must be para

Must have NH2 group for activity (or be converted in vivo) (HBD!!)

Replacing the benzene ring decreases or abolishes activity

Adding substituents decreases or abolishes activity

R = SO2NR’2 gives inactive compounds (HBD)

R can be any of the compounds shown in the picture but potency is reduced

96
Q

Describe the MOA of SERMs.

A

SERM stands for selective estrogen receptor modulator. They appear to act as estrogen agonists in the bone. They decrease bone resorption and turnover, along with increasing bone mineral density (BMD) and decreasing fracture incidence.

97
Q

Why are anthracyclines called antitumor antibiotics?

A

Because they’re isolated from microorganisms and used to treat cancer.

98
Q

______ was the first true homogenous HTS screening technology. How does it work?

A

SPA

The first bead (antibody/receptor) is unbound, so there will be no detectable light from the assay. Compounds that bind to the receptor will displace the radioligand. The moment the binding molecule comes to the bead, it transfers energy and the bead will light up. It will only light up if there’s good binding.

Another molecule may bind to the bread if it has a higher affinity than the first molecule. The purpose is to see how much your compound can reduce the signal. More reduction = better second compound

99
Q

What are the 3 therapeutic strategies for treating Alzheimer’s?

A

Amyloid hypothesis (inhibit plaque production/aggregation, clearance enhancer)

Cholinergic Hypothesis (cholinergic deterioration is responsible for loss of cognitive function, so this will maintain function for longer)

Treatment of behavioral and psychological symptoms.

100
Q

What other disease state (besides hyperglycemia) can SGLT2 inhibitors be used to treat? Why?

A

SGLT2 inhibitors can efficiently pull volume off patients (increasing excretion of glucose can have a diuretic effect), so they can also be used to help with heart failure.

101
Q

the most important class of inorganic chemical therapeutics by far is

A

cisplantin (platinum) acts by forming a covalent “complex” with guanine that leads to cytotoxicity and apoptosis

102
Q

Which topoisomerase 1 inhibitor causes diarrhea?

A

Irinotecan

103
Q

Small molecule drugs are approved via _____ with a ____ for new drugs and a ____ for generics.

Biologics are approved via _____ with a ____ for new drugs and a _____ for biosimilars.

A

FDCA
NDA
ANDA

PHSA
Biologics License Application
Biosimilar Biologics License Application

104
Q

SPECT is used for

A

visualizing vasculature

105
Q

What is the MOA of metaglinides?

A

Bind to ATP sensitive K channels on the cell membrane of pancreatic beta cells (like sulfonylureas)

106
Q

When do GLP studies take place?

What takes place in them?

A

After the initial exploratory studies.

Further toxicology studies in at least two animal species (1 rodent and 1 non-rodent)

Further genotoxicity studies (including in vivo in addition to in vitro)

Safety pharmacology studies continue, including reproductive toxicity studies

Toxicokinetic studies

107
Q

_____ is the process of converting an amine and a carboxylic acid to an amide.

It requires the use of ____________, specifically.

The combinatino potential outcome (number of products) is __________ (small, large?)

A

Amide coupling

requires a secondary amine specifically

has a large number of potential products (thousands of possible combinations)

108
Q

True or false: there were no generics allowed in the original 1938 FD&C Act, but the Kefauver-Harris Amendments allowed for all generic drugs to be approved.

A

FALSE
The Kefauver-Harris Amendments only allowed for generics for drugs approved before 1962 (the first ANDAs based on the literature)
The modern generic laws were passed in 1984 with the passage of the Drug Price Competition and Patent Term Restoration Act (aka the Hatch-Waxman Act)

109
Q

What is unique about teniposide (a topo 2 inhibitor) that makes it more potent than other drugs of its class?

A

it has a tienyl moiety (sulfur) that increases its lipophilicity, thus increasing its uptake and potency

110
Q

Amyloid precursor protein (APP) is the surface glycoprotein responsible for static cell-substrate adhesion and/or neurite growth. To be activated, it is hydrolyzed into smaller peptides. What disease is associated with the hydrolysis fo the protein by beta-secretase instead of alpha-secretase?

Which form is worse?

A

Alzheimer’s

A 1:10 ratio of AB1-42 to AB1-40 has the most inflammation potential

111
Q

Which SSRIs have active metabolites? Why is this clinically relevant?

A

Fluoxetine and Sertraline

they have more extended washout periods required if switching to other SSRIs or MAOIs (otherwise, can result in serotonin syndrome)

112
Q

When was an abbreviated approval pathway for biosimilars introduced?

A
113
Q

boronic acid is a bioisostere of _______. what is the result of using this bioisostere?

A

carboxylic acid boronic acid forms a covalent bond instead of a hydrogen bond (how COOH works), thus making it a suicide inhibitor

114
Q

What makes epirubicin less toxic than doxorubicin?

A

The 4’-hydroxy group on epirubicin is in the beta position and thus less prone to one-electron oxidation

115
Q

Identify the drug based on its MOA and structure:

an anionic surfactant that lowers the surface tension at the oil-water interface of feces, allowing water and lipids to penetrate the stool

A

Docusate (Colase)

116
Q

Which two type 1 statins are prodrugs?

A

Lovastatin and Simvastatin

117
Q

Identify the process shown in the picture.

A

Parallel synthesis

118
Q

What is an incretin? Give an example of an endogenous incretin.

A

Incretins are molecules that stimulate insulin release and inhibit glucagon release.
– thus, they can directly and effectively lower blood glucose

Example: glucagon-like peptide 1 (GLP-1)

119
Q

________ is a process that brings together validated, tractable targets and chemical diversity to rapidly identify novel lead compounds for early phase drug discovery.

What are some advantages of this process?

A

High Throughput Screen (HTS)

50-70% of new drug PROJECTS originate this way

Advantages:

  • validated, tractable targets (target selection for HTS)
  • industrialized (HTS assy technologies and automation)
  • chemical diversity (sample selection for HTS)
120
Q

What are the effects of bisphosphonates?

How are they able to do this?

A

They inhibit osteoclast proliferation, decrease activity, reduce life span, and (as a result) decrease the number of sites along the bone surface where bone resorption occurs.

This is possible because they mimic pyrophosphate and can bind to the hydroxyapatite portion of the bone, aka they can bind to and stabilize calcium phosphate effectively

121
Q

Which phase of cancer is the last one that is reversible with diet and lifestyle changes?

A

Promotion

122
Q

What issue arises with the use of ifosfamide?

A

It is a prodrug with two different isomers (S and R).

The S isomer is responsible for the formation of the actual alkylating agent (aziridine)

The R form causes nephrotoxicity because it can be converted to chloroacetaldehyde in the nephrons.

123
Q

What are the current principal laws that govern biologics?

A

the FD&C act and the 1944 Public Health Service Act

124
Q

Identify the two main approaches for the treatment of Multiple Sclerosis.

A

1st Approach: Modulate Immune & Inflammatory Responses

Immunomodulators - shifting the immune response (modulation of cytokine production; changes in immune cell proliferation, migration, and recognition; downregulation of the genes involved in immune responses)

Immunosuppressants - blocking of immune responses (antiproliferative agents mostly, also affect healthy cells causing cytotoxicity)

2nd Approach: Enhance Regeneration

Remyelination Agents - glatiramer acetate

125
Q

List some characteristics associated with Parkinson’s Disease.

A
  • mostly sporadic, rarely inherited
  • movement disorder
  • affects substantia nigra and hypothalamus
  • protein involved: alpha-synuclein
  • clinical features include resting tremor, disturbance of postures (falls), rigidity of muscle and joint motility, paucity or slowing of voluntary movement
  • Neuropathology - degeneration of pigmented neurons that produce dopamine and norepinephrine
126
Q

Identify the class of drug depicted in the photo.

What is it indicated for?

Describe the MOA.

Bonus: what specific drug is it?

A

NK1 Receptor Antagonist

Indicated for the prevention of nausea and/or vomiting

Used in combination with 5-HT3 antagonists

MOA - selective high-affinity antagonist of substance P/neurokinin 1 (NK1) receptors

Arepitant (EMEND)

127
Q

What is the MOA of metformin?

A

Decreases hepatic glucose production

Decreases intestinal absorption of glucose

Improves insulin sensitivity by increasing peripheral glucose uptake and utilization

128
Q

Sulfa drugs have 3 distinct activities. What are they?

A
  • antimicrobial
  • diuretic
  • antidiabetic
129
Q

Why do alkylating agents cause toxicity?

A

They are non-selective for cancer cells and will attack all rapidly dividing cells (like the skin)

130
Q

Describe the MOA of long-acting insulin.

A

Changes in AA sequence:

  • changes isoelectric point
  • adds two ARG to the COOH terminal of the B chain
  • prevents deamination of acid-sensitive asparagine by replacing it with glycine (at the 21 position on the A chain)
  • aggregation in the cutaneous space
131
Q

Define the revised rule of 5 for BBB penetration.

A

Sum of oxygen and nitrogen atoms < 6

ClogP - (N + O) > 0

PSA < 70 A2 (PSA = polar surface area)

MW < 450 Da

LogD = 1-3

132
Q

Tresiba and levemir both utilize changes to the amino acid in the 29th position on the B chain, but in different ways. What changes do they have?

A

Tresiba - hexadecanedioic acid conjugate to Lys on B29, allowing for the formation of multi-hexamers that causes slow release from tissues

Levemir - myristic acid conjugate to Lys on B29, allowing it to bind to albumin, from which it slowly dissociates

133
Q

Describe some features associated with statins.

A

Statins with hydrophilic character target liver cells and have lower side effects (ex. rosuvastatin); they don’t cross cell membranes easily so their liver uptake is OATP dependent

Lipophilic statins readily cross membranes and exert SE due to inhibition of HMGR in other cells (like muscle cells)

Common SE = myalgia (muscle pain)

134
Q

Identify the class of drug depicted in the photo.

What is it indicated for?

Bonus: name the drug.

A

Proton Pump Inhibitor

Indicated for short-term treatment of erosive esophagitis associated with GERD, maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger-Ellison syndrome.

Pantoprazole (Protonix)

135
Q

Can non-steroid based molecules be used to affect hormone levels?

A

Yes.

136
Q

What is lithium used for?

A
  • classic mood stabilizer
  • effectively used to control and prevent manic episodes in 70-80% of those with BPD as well as treat other forms of depression
  • those who respond to lithium for depression are those who have not responded to TCAs after several weeks of treatment
  • it is specific to the CNS because inositol can’t cross the BBB and replenish depleted inositol levels

_***the half-life is longer in older people, so you have to be more careful_

137
Q

Explain the SAR of tricyclic secondary amine antidepressants (NRIs).

A
  • the NRI tricyclic system revolves around the middle ring: it helps put the phenol rings in a specific spatial relation to one another (can’t be too flat, or they’ll have antipsychotic activity instead)
  • the middle ring is also important in terms of flexibility: more conformational motility = increased potency and selectivity
  • the secondary amine is what gives it selectivity for NET > SERT

**the high lipophilicity of tricyclic systems is what gives them the ability to block sodium channels and cause cardiotoxicity

138
Q

Describe what takes place during phase 1 of clinical studies.

A

Takes place over the period of 1 year with 25-100 healthy subjects

Analyzes:

  • metabolic actions in humans
  • pharmacologic actions in humans
  • side effects with increasing doses
  • effectiveness of drug
139
Q

What is the MOA of GLP-1 receptor agonists?

A

—tide

Exenatide (bydureon/byetta)
Liraglutide (victoza, saxenda)
Lixisenatide (lyxumia)
Albiglutide (tanzeum)
Dulaglutide (trulicity)
Semaglutide (ozempic)

140
Q

why are metals good for structural scaffolds?

A

they have greater valency and can accommodate more bonds

141
Q

Which natural molecule to bisphosphonates mimic? What is the difference between the two?

A

Bisphosphonates mimic pyrophosphate (a normal constituent of bone).
The oxygen in P-O-P (of pyrophosphate) is replaced with a carbon atom (in bisphosphonates) to create a non-hydrolyzable backbone.

142
Q

What type of anesthetics (amide or ester) possesses antiarrhythmic activity when given parenterally (via inhibition of Na channels in cardiac tissue)

A

Amide type

143
Q

Give examples of drugs that are structurally non-specific, with no specific site of action.

A

Gaseous anesthetics, sedatives, antiseptics

144
Q

Which drug is shown in the picture?

A

esomeprazole (nexium) – PPI

145
Q

Identify the drug in the picture. What class does it belong to?

A

Famotidine (pepcid)

H2 receptor antagonist

146
Q

What side effect is characteristic of all intercalating agents?

A

Myelosuppression

147
Q

Which drugs are S phase specific?

A 
Topoisomerase inhibitors (specificaly topo 1)
DNA chain terminators

Note - topo 2 inhibitors can act during early G2

148
Q

How do hyperthyroid treatment drugs work?

A

Methimazole, PTU, and Carbimazole (prodrug of methimazole) prevent iodine and peroxidase from interacting with thyroglobulin, thus preventing the production of T3 and T4.

M and C also interfere with the conversion of T4 to T3

149
Q

What are IND and NDA?

A

IND –> investigation new drug application that must be filed with the FDA before clinical trials can begin

NDA –> new drug application filed after phase 3 trials, before phase 4 can begin (covers safety, labeling, and quality control measures)

150
Q

The physiological function of a drug is a function of the ______

A

chemical constitution

151
Q

Why do anthracyclines have “rubicin” as the suffic?

A

They turn urine red.

152
Q

what useful property does boron possess?

A

it can exist as both tri and tetra valent it is also non-toxic

153
Q

What is the primary goal of phase 2 clinical studies?

A
  • determine short-term side effects and risks associated with the drug in patients with the disease or condition

takes 1-2 years and studies effects in 150-300 PATIENTS

154
Q

Describe (in detail) the MOA of SSRIs and their SAR.

A

SSRIs block SERT - serotonin reuptake transporters in order to:

  • extend duration of time over which 5HT (serotonin) is present in the synaptic cleft
  • allowing more 5HT to travel back and bind to 5HT-1A receptors that are on the presynaptic neurons (leading to desensitization of the negative feedback mechanism they usually provide)
  • SAR: the X and Y groups are EWGs, which give them increased selectivity for SERT vs NET as well as increased potency; there will be at least 3 carbons between the nitrogen and the aromatic ring
155
Q

With increasing Log P, what effects arise?

A
  • increased binding to enzyme/receptor
  • decreased aqueous solubility
  • increased binding to P450 metabolizing enzymes (not good)
  • increased absorption through membrane
  • increased binding to blood/tissue proteins (less free drug to act)
  • increased binding to hERG heart ion channel - cardiotoxicity risk
156
Q

Describe the structure in the picture, identifying the important aspects of its SAR.

A

It’s a catecholamine

The aromatic hydroxyl groups are required for H bonds to the target serine residues (especially in beta receptors)

The aromatic ring forms VDW interactions with the phenylalanine in the binding site

The alcoholic -OH forms H bonds with asparagine

The aminium ion forms an ionic bond with the aspartate

N-alkyl substituents lead to selectivity for beta receptors

157
Q

What does IRB stand for?

A

Institutional Review Board

158
Q

What is chorex?

What is it used for?

A

human chorionic gonadotropin (hCG)

  • indicated to cause ovulation and treat infertility in women
  • can be used to increase sperm count in men
159
Q

Why do irinotecan and topotecan have basic side chains on C10 and C9, respectively?

A

To increase water solubility

160
Q

Identify the class of drug depicted below.

Bonus: name each drug.

A

Second generation beta blockers.

Acebutolol, Atenolol, Metoprolol, Betaxolol

(Remember 1st, half of the alphabet are the selective beta blockers)

161
Q

The most commonly used type of drug therapy for depression is __________. Give examples.

A

SSRIs (selective serotonin reuptake inhibitors)

Sertraline

Fluoxetine

Citalopram

Trazodone

Escitalopram

162
Q

A compound that mimics or blocks the biological effect of a peptide, but without undesirable structural characteristics.

A

Peptidomimetics

163
Q

Define the terms pharmacophore, toxicophore, and auxophore.

A

Pharmacophore - the relevant group on the compound that interacts with the target to produce activity

Toxicophore - any constituent known to cause toxicity

Auxophore - the rest of the molecule (can be equally important in providing solubility, delivery, etc.)

164
Q

Describe some of the therapies used in the treatment of behavioral and psychological symptoms of Alzheimer’s Disease.

A

Serotonin Reuptake Inhibitors: fluoxetine, sertraline, paroxetine (used to treat comorbid depression)

Antipsychotic Agents: olanzapine, aripiprazole, ziprasidone (to treat agitation/aggression)

Benzodiazepines: to treat anxiety and agitation; trigger further agitation, rapid cognitive, and functional decline

165
Q

What much DNA alkylating agents contain (structurally speaking)?

A

must have electrophilic centers with good leaving groups

  • the general structure is an R group with the central molecule (electrophile) attached to two leaving groups
166
Q

Explain how regular insulin therapy works.

A

Exogenously delivers the insulin, replacing the insulin that’s missing.

  • it’s noted by an R on the label.
167
Q

Which drugs are intercalting agents?

A

anthracycline
etoposide (topo 2 inhibitor)
irinotecan (topo 1 inhibitor)
topotecan (topo 1 inhibitor)

168
Q

Why might a patient not realize the full impact of codeine-based analgesics and require an alternative therapy?

A

Poor CYP2D6 metablizers don’t feel the full effects

169
Q

What problems may arise with rational drug design?

A
  • cannot predict toxicity/side effects
  • cannot predict transport/distribution
  • cannot predict metabolism
170
Q

Based on what is required for antimicrobial activity of sulfa drugs, identify the type of drug for each molecule in the picture.

A
171
Q

Which two classes of drugs are antiemetics?

A

5-HT3 receptor antagonists and NK1 receptor antagonists

172
Q

What class of drug does Amitiza belong to?

What is it indicated for?

Describe its MOA.

A
  • Chloride Channel Activator
  • indicated for use in treatment of chronic idiopathic constipation in adults and for treatment of IBS-C
  • MOA: locally acting chloride channel activation that enhances a chloride-rich intestinal fluid secretion (this increases the motility)
173
Q

the three approved platinum based treatments for cancer include

A

carboplatin, oxaliplatin, and cisplatin

174
Q

Why is non-clinical research done?

A

to demonstrate that the drug is reasonably safe for use in initial small-scale clinical studies.

175
Q

Describe the SAR of the molecule in the photo. Which drug is depicted?

A

Enalaprilat

The carboxylate ion weakly binds with the zinc cofactor found in ACE.

  • the weaker interaction of the carboxylate is compensated for by extra binding interactions involving phenethyl and methyl groups
  • the phenethyl group fits into the S1 pocket and the methyl group fits into the S1’ pocket
  • the amine mimics the amide of the natural substrate

Bonus: enalapril is an ethyl ester prodrug for enalaprilat

176
Q

Describe the mechanism of action of proton pump inhibitors.

A

They form a covalent bond with their target receptor (proton pumps).

The sulfoxide group and a nitrogen group (that is a couple carbons removed from it) allow the structure to be arranged in such a way that it can form a disulfide bond with its traget.

They inhibit the final step in gastric acid production. In the gastric parietal cells, they bind to the H+/K+ ATP pump to inhibit secretion. The covalent binding prevents secretion for up to 24 hours or longer.

177
Q

What is the MOA of acarbose?

A

Acarbose is an alpha-glucosidase (glycoside hydrolase) and pancreatic alpha-amylase inhibitor
– thus, it blocks enzymes that digest carbohydrates in the small intestine, decreasing the rate at which carbohydrates are broken down into glucose

178
Q

What pathological features and clinical features are associated with Alzheimer’s Disease?

A
  • neuritic plaques
  • neurofibrillary tangles
  • structural atrophy of the brain
  • progressive dementia

protein involved - amyloid beta and tau

179
Q

When a secondary amine reacts with an aldehyde and results in loss of water, what kind of reaction has just occured?

A

Reductive amination

(oxygen on the ketone takes a hydrogen from the secondary amine and a hydrogen from the carbon of the ketone to leave as water); the resulting molecule has a tertiary amine

180
Q

What was the final force behind a meat inspection law and comprehensive food/drug law that eventually led to the passage of the 1906 “Federal Food and Drugs Act”?

A

Upton Sinclair’s “The Jungle”

181
Q

When can you submit an IND?

A

Once you have the basic chemistry and have completed animal trials (before human trials)

182
Q

Which form of cross-linking can be easily removed?

A

Intrastrand (on the same strand)

183
Q

Identify the MOA of flupirtine.

A

non-opioid, non-NSAID that can prevent bradykinin release

(binds to potassium channels and prevents them from opening, this stops the production of the pain response)

184
Q

What cofactor is found in the ACE enzyme?

A

Zinc

185
Q

Why is L-dopa given instead of just plain dopamine (in the efforts to increase dopamine in the brain)?

What is given alongside L-dopa?

A
  • dopamine doesn’t cross the BBB (it has too many hydrogen bond donors)
  • L-dopa (1%) is able to penetrate the BBB and will be decarboxylated into dopamine upon penetration

Carbidopa is given with L-dopa (levodopa) because carbidopa is a competitive inhibitor of decarboxylases, so it selectively prevents the decarboxylation of L-dopa outside of the CNS

186
Q

Define homologation. What are the two possible explanations for it?

A

Homologation = increasing compounds by a constant unit (ex. addition of CH2 to elongate)

PK Explanation - increasing chain length increases lipophilicity and the ability to cross membranes; if it’s too high, it remains in the membrane

PD Explanation - hydrophobic pocket increases binding with increasing length; too large and does not fit into the hydrophobic pocket

187
Q

What is the purpose of CMC (chemistry, manufacturing, and controls)?

A
  • assure that the drug sold will have quality attributes similar to those of the drug demonstrated to be safe and effective (meaning the ones being produced have the same quality attributes as the ones that were tested/approved)
  • assure the quality meets appropriate standards and is consistent
  • assure the drug you are using is the one described on the label
188
Q

What two drugs are based on the hormone vasopressin (ADH)?

A

Pitressin and Vasostrict

189
Q

_______ enables identification of the biomolecular targets of efficacious agents with unknown mechanisms of action

A

Reverse Pharmacology

190
Q

What are CDER and CBER?

A

The center for drug evaluation and research (for small molecule)

The center for biologics evaluation and research (for biologics)

191
Q

What class of drug is depicted in the picture?

Bonus: name the drug molecules.

A

SSRIs

Left to right: citalopram, fluoxetine, paroxetine, sertraline

192
Q

Biological assays used in HTS must be…

A

Robust

Reliable

Cost-Effective

Simple & User-Friendly

Generic

Amenable to Automation

Have the Potential for Miniaturization

193
Q

Give examples of drugs that are part of the 5-HT3 antagonist class.

A

Zofran (ondansetron) and Kytril (granisetron)

194
Q

List some drugs found in the PPI class.

A

Omeprazole (Prilosec)

Lansoprazole (Prevacid)

Pantoprazole (Protonix)

Esomeprazole (Nexium)

195
Q

Identify the class of drug depicted in the photo.

What is it indicated for?

Bonus: which drug is it?

A

5-HT3 Antagonist

Indicated for prevention of nausea and/or vomiting

Ondansetron (Zofran)

196
Q

__________ provides a protein “profile” that can be used to compare healthy and diseased states. What else can it provide?

A

Proteomics

Can provide comparative analysis of protein profiles of healthy and diseased states with profiles post drug treatment

197
Q

Which drugs function as dopamine receptor agonists?

A

Pramipexole and Ropinirole

198
Q

What is combinatorial chemistry and what are the 3 most commonly used reactions?

A

it is the process of building a library of compounds/reactions

The 3 most common used reactions are amide coupling, sulphonamide formation, and reductive amination

199
Q

What is reglan indicated for?

A

Short-term treatment of GERD in adults who fail to respond to conventional therapy

Relief of symptoms in adults with acute and recurrent diabetic gastroparesis

200
Q

Identify the type of molecule that binds to each of the following opioid receptors:

Mu

Delta

Kappa

NOP

A

Mu - endorphins, enkephalins, endomorphins

Delta - only enkephalins

Kappa - dynorphins

NOP - nociceptin

201
Q

What are the critical elements in CMC?

A
  • how and where is the drug made?
  • how are the raw materials tested and monitored?
  • what control procedures are in place to assure product consistency and quality?
  • are the quality attributes adequately identified and characterized for the product?
  • are the test methods used to monitor the product quality appropriate?
  • how long does the product maintain its quality after it is made (shelf-life/expiry)?
202
Q

Describe the MOA of tricyclic SNRIs.

A

SNRIs block both serotonin and norepinephrine reuptake.

  • tertiary amines (if secondary they’d be NRIs)
  • MOA: increased levels of 5HT and NE in cleft
203
Q

fluorodeoxyglucose is used in association with

A

PET scans

204
Q

What suffix is associated with SGLT2 inhibitor drugs?

Give at least 1 example of an SGLT2 inhibitor.

A

—gliflozin

Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)

205
Q

Which drug is shown in the picture?

What class does it belong to?

What is it indicated for?

A

Ranitidine (Zantac)

H2 receptor antagonist

Indicated for short-term treatment of active duodenal ulcer and treatment of GERD

206
Q

Which drugs are guanylate cyclase-C (GC-C) agonists indicated for use in treatment of IBS-C and chronic idiopathic constipation?

A

Linzess (linaclotide)

207
Q

What are the 3 classifications of anti-cancer drugs?

A

Immunotherapy

Chemotherapy

Hormonal therapy

208
Q

What structure is pictured below?

Why is it important?

A

2-aminothiazide privileged structure

when it is present in a drug molecule, it is part of the pharmacophore and any modifications to the structure will result in loss of activity

209
Q

What structure is pictured below?

Why is it important?

A

Barbituric acid privileged structure

when it is present in a drug molecule, it is part of the pharmacophore and any modifications to the structure will result in loss of activity

210
Q

What structure is pictured below?

Why is it significant?

A

Benzo privileged structure

when it is present in a drug molecule, it is part of the pharmacophore and any modifications to the structure will result in loss of activity

211
Q

FLIPR stands for…

What is it used for?

A

Fluorescent Imaging Plate Reader

Used for HTS calcium flux assays and ion channel screening (compounds block the enzyme, the enzyme cannot cleave the substrate, you don’t get a signal)

212
Q

An example of an HT radioligand binding assay is

A

SPA - scintillation proximity assay

213
Q

What was the purpose of performing these bioisostere modifications?

A

By first flipping the carbonyl and amine it prevents the peptide from being cleaved (it increases the stability because the enzyme (peptidase) no longer knows where to bind to cleave it)

214
Q

What makes boronic acid bioisosteres (of carboxylic acids) special?

A

They introduce covalent binding, thus making suicide inhibitors

215
Q

Define the purposes of each portion of the local anesthetic drug compounds including:

  • lipophilic portion
  • intermediate linker portion
  • hydrophilic portion
A

Lipophilic portion - helps penetrate the membrane

Linker chain - defines the stability of the compound

Hydrophilic portion - interacts with the sodium channel because it’s being protonated

216
Q

There are some allergic reactions associated with which structures on local anesthetics?

A
  • the para aminobenzoic acid compounds
  • ester linkers are less likely to produce toxicity than amide linkers
217
Q

Identify the common metabolic reactions associated with analgesics.

A

N-dealkylation by CYP3A4 - metabolites have limited clinical relevance because of the the reduced lipophilicity and agonist-promoting hydrophobic interaction with the receptor.

O-dealkylation by CYP2D6 - of the 3-methoxy group; required to generate the phenolic OH group essential for mu-receptor binding

Phase 2 metabolism prior to excretion

Final Exams Spring 2020 (2 decks)

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