Medicinal Chem Flashcards
1
Q
What is the definition of medicinal chemistry?
A
Multidisciplinary science concerned with the design + synthesis of new chemical entities in order to produce new medicines for the prevent and cure of disease
2
Q
Where is cholesterol made in the body
A
Liver at night
3
Q
Why is cholesterol important and why can too much be bad?
A
Needed for membrane fluidity and permeability and is an important precursor for the manufacture of steroids and vitamin D. Too much can block arteries and may be linked To cardiovascular disease
4
Q
What are LDLs
A
Low density lipoproteins - carry cholesterol around the body
Once level is too high ldl receptor is blocked so no cholesterol in the form of LDL can be taken up
5
Q
What are the key stages in drug development
A
KS1 - disease studied and drug target identified
KS2- lead discovery
KS3 - lead optimisation
KS4 - preclinical studies
KS5- clinical trials and marketing
6
Q
What is a lead compound?
A
A synthetically accessible chemical entity that produces the desired pharmacological activity
Must have suitable chemical and physiochemical properties
7
Q
What the types of sources adopted to find the lead compound
A
Screening natural products or synthetic libraries
8
Q
Why are few lead compounds not ideal?
A
Low selectively and activity and significant side effects
9
Q
How can drug target interactions be improved
A
Once important binging sites and pharmacophores have been identified then synthetic analogies can be made
10
Q
How can development attrition be reduced?
A
By optimising drug like properties of lead compound at early stages of development
11
Q
What are drug like Properites
A
Once a that show acceptable ADME properties and taxicory properties in addition to desirable pharmacological properties
12
Q
What is the dosage form?
A
They way in which medicine is administered
13
Q
Give the three physical natures of the dosage forms
A
Liquids - emulsion, solutions and suspensions
semisolid formulations - gels and creams
Solid - capsules and tablets
14
Q
What does the dosage form contain
A
The active ingredient and excipients
15
Q
What are excipients
A
They are other ingredients that have a number or functions
Filler, binders, lubricants and preservatives and antioxidants
16
Q
True or false - changing the nature of the excipients can significantly affect the release of the active ingredient from the dosage form?
A
True
17
Q
What is the enteral route
A
Drugs absorbed through alimentary canal, rectal and sublingual routes (tissues in the tongue)
Unabsorbed material excreted through gastrointestinal tract
Make sure it doesn’t react inadvertently with food
18
Q
Fescues the parental route?
A
Avoids the GT and administered by injections, intravenously or nasal sprays and inhalers
Excrete via kidney (urine) or lungs
Faster therapeutic effect
19
Q
What are barriers to drug delivery?
A
Stomach - enzymes acids
GI- permeability and plasma proteins
Kidneys
Liver - metabolisms and bilateral excretion
20
Q
True or false - the structural properties do not govern the physichemical and biochemical Properites of the drugs
A
False
21
Q
What’s is lipophilicity?
A
The ability to dissolve in days, oils, lipids and non polar solvents
22
Q
What happens if a compound is too lipophilic
A
May not dissolve in aq media and will bind too strongly to plasma proteins
May distribute in lipid bilayer and not cells
23
Q
What happens is a compound is too polar
A
May not be absorbed by gut wall
24
Q
What is the partition coefficient
A
A measure of the way a compound distributes itself among two immiscible solvents
25
What is the most common organic phase when measuring partition coefficients
Octanol
Because it has a polar and non polar region so mimics lipid bilayer
P is easy to measure and correlates well with biological Properties
Predicted accurately using computational methods
26
What does it mean if P is greater or less than 1
P>1 (log P >0) more lipophillic
P<1 (log P<0) more hydrophilic
27
What is the distribution coefficient
The effective lipophilicity of a compound at a given pH
28
Why is log D a better way of measure he lipophilicity of a compound
It takes into account that things ionise in aq solution as well as a function of the lipophilicity of the un ionised compound and the degree of ionisation
29
What is pharmacokinetics (PK)
The study of how a drug reaches its target and what happens during its journey
30
What does ADME
Absorption
Distribution
Metabolism
Excretion
31
What is pharmacodynamics?
Studies drug effect on the body (efficacy and toxicity)
32
What is adsorption?
Absorption through the gastrointestinal tract into circulatory system
Occurs in small intestines due to large surface area
Once in cell it is protonated so it can't leave
33
What are P- glycoproteins and how can they reduce the bioavailability of a drug
They a efflux transporters and pimp put cytotoxic material out of cell. They are ATP driven and have a broad specificity so can remove drug from entering the cell.
34
How can the bioavailability of a drug be increased involving Pgp
Co administration with another compound that inhibits p- go
35
how does the drug bind with plasma proteins?
reversibly binding via H, dipole dipole and electrostatic int.
Dynamic equlibrium formed between bound and free drug in blood.
too much binding reduces its bioavailability
36
True or false: Acids and bases bind to the same site on Plasma proteins
false - they bind to different sites
37
How does Log D relate to plasma protein binding?
for basic and neutral drugs log d is proportional
it is higher for acids
the higher log d is the higher the binding
38
How are compounds distributed into cells?
pH gradient, Tissue pH is slightly lower than plasma pH. Basic compounds are distributed more into tissues than acidic compounds
39
what is metabolism?
the chemical reactions responsible for the conversion of the drug into other compounds either before or after it has reached site of action
40
Can metabolism occur via more than 1 route?
yeah more than 1 enzyme controlled routes.
41
What are the two different reactions that occur in metabolism?
Phase 1 and Phase 2
42
How can the speed at which a drug is metabolised have an effect on the bod?
Poor or slow metabolism - toxic
| fast and extensive metabolism - poor activity
43
what are phase 1 reactions and where do they occur?
Oxidation, reduction and hydrolysis. In the liver mainly but also the gut wall and blood plasma
44
describe phase 1 oxidation?
Carried out by P450 enzymes, these contain a Heam protein.
Fe(III) in resting state. Reduced to Fe(II) by 1 electron ET. Oxygen reacts and a reactive oxygen species made by another ET. This can then react to form the appropriate product
45
describe phase 1 reduction?
Nitro groups to Amines or hydroxylamines N(OH)Rn
| carbonyls to alcohols, ketones and aldehydes
46
describe phase 1 hydrolysis?
Amides/ esters to amines, alcohols and acids
47
what are phase II reactions and where do they occur?
Conjugation reactions
The addition of a group or molecule to the drug or metabolite.
In the liver
48
How do phase II reactions increase excretion rate?
the conjugated product is more polar
49
how are drugs and metabolites excreted from the body?
By the kidney and both via the same mechanism
50
what increases the likelihood of something being excreted?
the more polar or water soluble it is
51
describe the processes that occur in renal excretion?
1. anything not bound to plasma protein is filtered in the glomerulus
2. Can be excreted into urine along proximal tubing
3. Unionised compounds can undergo passive re absorption from urine into blood along the length nephron
4. Bound drug and metabolites will not be filtered.
52
what is the biliary excretion?
Transporters in liver tissue mediate the uptake of drugs and drug metabolite into tissue and efflux into bile. Bile builds up in gall bladder and released into intestine upon food uptake.
53
Can the drug be reabsorbed in biliary excretion?
Yes through Gastrointestinal tract
54
Why does the concentration of the drug decrease over time?
Metabolism and potentially excretion
55
What does AUC mean and what does it measure
Area under curve
| measures drug exposure
56
What does the therapeutic window indicate?
Safety of the drug, the bigger it is the safer the drug is
57
what does the volume distribution tell us (Vd)?
how widely the compound is distributed around the body
58
How is Vd measured?
Vd= Dose (mg) / plasma conc (mg/L)
59
How would Vd change if applied to the real world? eg a person
Vd = (Dose/plasma conc) / Body weight in Kg
| L/Kg
60
how is the clearance measured?
Dose (mg) / AUC
61
What does PO and IV mean?
drug is orally administered
| Intravenously administered
62
what and how is the half life measured?
Half life - is the time it takes for the concentration of a drug in systematic circulation to be halved
0.693/ clearance
63
What is bioavailablity ?
The fraction of the dose that reaches circulation unchanged I.e the ability of the drug to pass through the GI to plasma
64
How is bioavailablity measured?
%F = (AUC orally / AUV iv) * (DOSE iv / DOSE po ) * 100%
65
What is the minimum bioavailablity for drugs?
20%
66
what are types of intermolecular forces are there between drugs and their target?
```
Electrostatic/ ionic
hydrogen bonding
dipole dipole
VDW
Hydrophobic interactions
```
67
what type of intermolecular forces: Strongest type of intermolecular forces and are between oppositely charged groups
electrostatic/ionic
68
what type of intermolecular forces: strength depends on distance
Electrostatic/ ionic
69
what type of intermolecular forces: Stronger in hydrophobic environments
Electrostatic / Ionic
70
what type of intermolecular forces: Between electron deficient H and electron rich heteroatom?
Hydrogen Bonding
71
what type of intermolecular forces: interaction involves orbitals and is directional
Hydrogen bonding
72
what type of intermolecular forces: The angle between the acceptor and donor is 180
Hydrogen bonding
73
what type of intermolecular forces: Formed between areas of high and low electron densities leading to temporary dipole
VDW
74
what type of intermolecular forces: the strength of the interaction decreases rapidly with distance
VDW
75
what type of intermolecular forces: entropy decreases as water molecules form an ordered layer around the "X" surface?
Hydrophobic
76
what type of intermolecular forces: When "X" drug interacts with its target, water molecules are free and there is an increase in entropy
Hydrophobic
77
what type of intermolecular forces: Aromatic and large organic groups exhibit this force
Hydrophobic
78
what are enzymes?
Globular proteins that act as biologically catalyst, they speed up the rate at which equilibrium is met
They lower the activation energy
79
What is the active site
Hydrophobic clefts on the surface of enzymes
| They are made of amino acids that bind reactants and catalyses the reaction
80
what is the ideal relationship between an enzyme and the substrate
Strong enough to hold the substrate but weak enough to allow product depart
81
how do drug designs exploit the active site and substrate relationship
strong binding to inhibit the enzyme
82
How does the active site catalyses the reactions?
Acid base catalysis
83
How do acidic amino acid catalyse reaction in enzymes
Histidine contains an imidazole ring which is a weak acid. It exist as an equlibrium between its protonated and deprotonated state - act as a proton bank
84
How do basic amino acids catalyse reactions in enzymes?
Serine and cysteine contain nucleophillic residues (OH and SH respectively). These can react with substrate to form intermediates that might not necessarily be formed in the uncatalysed reaction providing an alternative route which may avoid high energy intermediates.
85
what is competitive inhibition (reversible inhibition) of enzymes?
The substrate and the active site are similar in shape.
The substrate binds reversibly through inter molecular interactions
the degree of inhibition depends on the strength of binding and conc of drug
binding of the drug prevents reaction from taking place
Increasing the concentration of substrate reverses this effect
86
what is non competitive inhibition of enzymes (irreversible)
Drug binds to active site irreversibly by covalent bonds
Substrate blocked so reaction can not take place
Increasing the concentration does not reverse the effect
87
what is allosteric inhibition of enzymes?
Drug reversibly binds to an allosteric binding site. Once bound an induce fit occurs which alters the shape of the active site and allosteric site.
Increasing the conc does not reverse the effect
drug and active site not similar in shape
88
what are agonists?
Bind to receptor and activate them. Mimic natural receptors
89
what is (reversible) competitive antagonist?
The messenger molecule and the antagonist are similar in shape.
The antogonist binds reversibly through inter molecular interactions with binding site
the degree of inhibition depends on the strength of binding and conc of drug
binding of the Antangonist prevents activation of receptor
Increasing the concentration of messenger reverses this effect
90
What is non competitive antagonism?
Antagonism binds to binding site irreversibly by covalent bonds
messenger blocked so receptor not activated
Increasing the concentration does not reverse the effect
91
what is allosteric antagonism?
Antogonism reversibly binds to an allosteric binding site on receptor. Once bound an induce fit occurs which alters the shape of the binding site and allosteric site.
Increasing the conc does not reverse the effect
Antagonism and binding site not similar in shape
92
what is antagonism by umbrella effect?
Antagonist binds reversible to a neighboring site. Bind via intermolecular bonds. Antagonist overlaps with binding site and blocks the messenger from binding.
93
How to reduce compounds block hERG receptor?
Reduce lipophilicity, basicity and the number of Oxygen hydrogen bond acceptors
94
What is SAR
structure activity relationship - Identify which functional groups are responsible for binding/activity
95
How does SAR work?
Alter, modify and mask functional groups and test analogue for activity and do in vivo and in vitro tests.
In vivtro - activity decreases then, group important
In vivo - activity remains the same then it not important
96
what are the analogues for alcohol groups
Ether and esters - no HBD and bulky groups (acyle) pose sterin hindrance meaning that weakened HBA
97
what type of interactions do Amines have?
Prim, secon and tert all HBA
prim and sec are HBA
protonated forms can have ionic interaction with carboxylate group on drug
98
What are analogues of amine that allows you to figure out if there is hydrogen bond interaction in binding or an ionic one
Convert prim and sec to amides - Gets rid of HBA as lp inteacts with carbonyl
Steric interaction with acyl reduces HBA property
Converting to amide prevent protonation so no ionic interaction
99
what is the role of quanternary ion salts in SAR
they form ionic interactions with carboxylates
| can form induced dipole interactions with aromatic rings, the positive Nitrogen distorts pi electrons
100
what interactions do you get with carboxylic acids?
HBA and HBD - can exist as a carboxylate then you get ionic int. CA ion good ligand for Zn.
101
What can analogues of CA tell us about the role of functional group in SAR?
turn to esters and alcohol. Neither can ionize. Alcohol will tell us if the carbonyl C=O is involved in bonding
102
what interactions do ketones/aldehydes have?
Ketones are planar so HBA
| lone pairs in sp2 hydridised orbitals so get dipole dipole interactions
103
What can analogues of ketones and aldehydes tell us about the role of functional group in SAR?
convert it to alcohol, tetrahedral geometry (sp3) weakens HB interactions and dipole dipole int.
104
what interactions doe ester have?
HBA - Carbonyl O more likely to be HBA than alkoxy
105
What can analogues of esters tell us about the role of functional group in SAR?
Alcohol - importance of C=O
| carboxylic acids - hydrolysis gives CA and OH may lead to decrease of activity due to loss of functional group
106
what interactions do amides have?
depending on if primary, secondry or tertiary amides it will be HBD or HBA
107
What can analogues of amides tell us about the role of functional group in SAR?
If convert to COOH - HBD
Convert to amine - HBA
Methylate the hydrogen and its no longer a HBD and steric interaction prevents HBA
108
what interactions do alkyl groups?
VDW interactions with hydrophobic tissue
109
what is a pharmacophore?
Defines the important groups in binding and relative positions of binding groups
110
What does a 2D pharmacophore give?
Minimum skeleton connecting important binding groups
111
What does a 3D phamacophore tell you?
defines relative positions in space and important
112
what are the reasons to optimise binding interactions
Increase activity and reduces dosage levels
| increase selectivity to reduce side effects
113
How can varying the alkyl groups optimise binding interactions?
In lead compound alkyl groups interact with hydrophobic region in binding site. If you vary length and bulk of group to
114
what are the strategies in optimising binding interactions?
```
Vary alkyl groups
Vary aryl substituents
extra functional groups
Extend chain length
ring variations
```
115
what are isosteres?
Replacing functional group with another group of the same valency eg OH with SH, NH2 and CH3
116
why are isosteres useful?
They lead to more controlled steric and electronic effects
117
what are bio-isosteres
replacing a functional group with another group that retains the same biological function
118
Why must a drug be polar?
so it is soluble in aqueous conditions
| To interact with molecular targets
119
Why must a drug be "fatty"
Absorption across the lipid bilayer
| To avoid rapid excretion
120
what are prodrugs?
Inactive compound converted to active compound in the body
121
why are produgs useful
They increase membrane permeability and prolong activity
122
how are prodrugs used to increase membrane permeability?
Esters, mask polar groups CA. better absorption into GIT. Esterase hydrolyses them into CA. Leaving group should be something that isnt toxic eg EtOH
123
How are amines improved for better membrane permeability
Methylate amines to reduce the polarity
| Dimethylated in the liver
124
what is the trojan horse strategy?
prodrugs designed to mimic bio synthetic building block and transported across membrane by carrier proteins
125
What is the stecker and amidomalonate synthesis?
alpha amino acids
stecker - aldehyde, HCN and NH3
In amidomalonate - base deprotonates aplha C, Addition of Rx and then removal of protecting groups
126
Give the strucuture of coupling reagents?
DCC, DIC, EDC
127
what are three protecting groups for amines and how are they removed?
Fmoc (piperidine) , Obz ( mild acid or hydrogenolysis), T- boc ( mild acid)
128
How is the merifold resin removed from the synthesis
HF
129
How is the merifold resin removed from the synthesis
HF
130
How is the wang resin removed?
TFA cleavage
131
give the cobinatorial synthesis - mix and split method
Bead in seperate vials
First amino acid added - bead bound to amino acid
Then mix and split and add amino acid - dipeptide
repeat
