Drug Discovery Flashcards
1
Q
What are the different Discovery and Development Processes?
A
Chemical Synthesis/Natural products/Molecular modeling
Preclinical Testing
Clinical Testing
Marketing
2
Q
What is in vitro testing?
A
In a controlled environment outside of a living organism.
3
Q
What is in vivo testing?
A
In whole, living organism. ex: humans and animals
4
Q
Once a drug is judged to be ready to be studied in humans what document what must be filed?
A
Investigational New Drug (IND)
5
Q
With what organization must the IND be filed with?
A
Food and Drug Administration (FDA)
6
Q
What are the steps of Drug Discovery?
A
Clinical Testing
Phase 1
Phase 2
Phase 3
7
Q
If phase 3 results meet expectations what document must be filed with the FDA?
A
New Drug Application (NDA) or Biological License Application
8
Q
When does phase 4 begin?
A
After the drug is approved for sale in the market
9
Q
What are some sources of new drugs?
A
Natural Products - plants, micro organisms, based on mammalian biochemical pathways, other sources
Synthetic Products
10
Q
Digoxin is made from?
A
leaves of a foxglove plant
11
Q
Digoxin is used for?
A
congestive heart failure (CHF)
12
Q
Quinidine is made from?
A
bark of Cinchona tree
13
Q
Quinidine is used for?
A
Anti-arrhythmic agent
14
Q
Quinine is used for?
A
Antimalarial
15
Q
Quinine is made from?
A
bark of Cinchona tree
16
Q
Opioid alkaloids are made from?
A
opium poppy
17
Q
Opioid alkaloids are used for?
A
pain
18
Q
Camptothecin is made from?
A
the bark and stem of camptotheca/happy tree
19
Q
Camptothecin is used for?
A
Anticancer agent
20
Q
The chemical class of digoxin is?
A
Steroid glycoside
21
Q
The therapeutic class of digoxin is?
A
positive inotropic agent
22
Q
Quinidine and Quinine are what kind of stereoisomers?
A
Diastereomers
23
Q
The chemical class of Quinidine and Quinine are?
A
Alkaloid
24
Q
The therapeutic class of Quinidine is?
A
Class I Anti-arrhythmic agent
25
The therapeutic lass of Quinine is?
Antimalarial agent
26
The chemical class of opioids are?
Opioid alkaloid
27
The therapeutic class of opioids are?
Opiate analgesic
28
The chemical class of Camptothecin is?
Quinoline alkaloid
29
The therapeutic class of Camptothecin is?
Anti-cancer
30
What are the biochemicals?
Neurohormones, peptide hormones, sex hormones, adrenal hormones, prostaglandins, antimetabolites, and others.
31
What are examples of neurohormones?
adrenaline, levodopa, and histamine
32
What are examples of peptide hormones?
insulin and glucagons
33
What are examples of sex hormones?
estrogens, progesterone, and testosterone
34
What are examples of adrenal hormones?
hydrocortisone and aldosterone
35
What are examples of prostagalndins?
prostaglandin E1 and E2
36
What are examples of antimetabolites?
5-fluorouracil design based on uracil
37
What is a natural product of epinephrine?
adrenaline - sympathomimetic amine isolated from adrenal gland used to treat anaphylactic shock, cardiac failure, glaucoma etc.
38
What is a natural product of erythropoietin?
epogen, aranesp - renal glycoprotein which stimulates red blood cell production.
39
What is a natural product of Insulin?
humulin - replacement of insulin normally produced by the islet cells in the pancreas to manage type I diabetes.
40
What is a natural product of levothyroxine sodium?
synthroid - replacement of thyroid hormone in hypothyroid patients.
41
What are different drug discovery approaches?
Drugs discovered without a lead molecule, drugs based on natural products, random screening, rational drug design, drug metabolism studies, observation of side effects.
42
What are examples of drugs discovered without a lead molecule?
penicillin and chlordiazepoxide (Librium)
43
Who discovered penicillin and how?
Sir Alexander Fleming discovered penicillin in 1929 from a microorangism. Accidental Discovery
44
What is the therapeutic class of penicillin?
Antibacterial agent
45
What is the chemical class of penicillin?
Beta-lactam
46
What is the mechanism of action of penicillin?
Inhibits bacterial cell wall synthesis by inhibiting penicillin-binding proteins (PBP). Mammalian cells don't contain a cell wall!!!
47
What are PBP's?
Penicillin-binding proteins are enzymes that are important in bacterial cell wall formation and remodeling by transpeptidation (cross linking)
48
What are other beta-lactam antibiotics?
penicillin's, cephalosporin's, carbapenem's, monobactam's, beta-lactamase inhibitors.
49
What are examples of antibacterials?
Cephalosporins, aminoglycosides, tetracyclines, and polyketides.
50
The therapeutic application of microbial metabolites lead to discovery of what?
cholesterol lowering agents
immunosuppressive agents
anticancer agents
51
Who discovered chlordiazepoxide and how?
Dr. Sternbach at Hoffman LaRoche synthesized a series of quinaoline N-oxides. They did not yield good pharmacologic effects. One compound from this category (quinazolone-3-oxides) crystallized out and was found to have hypnotic, sedative and muscle relaxant activities.
52
What does aspirin inhibit?
COX forms an irreversible covalent bond.
53
What chemical class is chlordiazepoxide found in?
Benzodiazepine (first one)
54
What was chlordiazepoxide marked as in 1960?
As Librium, a safe and effective anxiolytic agent.
55
What drug was made when chlordiazepoxide was structurally modified?
Diazepam (3 to 10-fold more potent than chlordiazepoxide)
56
What is the therapeutic class of chlordiazepoxide?
Anti-anxiety agent
57
What is the mechanism of action for chlordiazepoxide?
GABAa receptor agonist, potentiates neuronal inhibitory actions of GABA
58
What is GABA?
An important inhibitory neurotransmitter in the brain.
59
Aspirin is a drug based on a _______.
natural product.
60
Where is aspirin derived from?
Willow bark
61
What is the chemical class of aspirin?
Aromatic carboxylic acid
62
What is the therapeutic class of aspirin?
Minor aches and mild to moderate pain.
Arthritis and related arthritic conditions.
Reduces the risk of transient ischemic attacks.
Myocardial infarction prophylaxis.
Platelet aggregation inhibitor.
63
What occurs in ester hydrolysis?
An ester in the presence of water will change to a Carboxylic Acid and an alcohol.
64
What is an important quality for an antibacterial agent to have?
selectivity
65
What does PABA stand for?
p-aminobenzoic acid
66
What is the enzyme responsible for binding to PABA?
Dihydropteroate synthase
67
What is the MOA of sulfanilamide?
Competes with PABA by binding to Dihydropteroate synthase and thus blocking the biosynthesis of folic acid. This makes it an antibacterial agent.
68
What is a side effect of terfenadine?
cardiacarrhythmias
69
What are the similarities and differences of terfenadine and fexofenadine?
Terfenadine was the original discovered drugs. Fexofenadine is a metabolite of terfenadine. They are both antihistamines. Fexofenadine does not have the side effect of cardiacarrhthmias unlink terfenadine. Fexofenadine has a Carboxylic Acid.
70
How was sildenafil citrate (Viagra) discovered?
Observation of side effects. It was originally being tested to treat angina.
71
What is the therapeutic class for sildenafil citrate?
Treatment of ED and pulmonary arterial hypertension
72
What is the chemical calls of sildenafil citrate?
Pyrazolo-Pyrimidine
73
What is the mechanism of action for sildenafil citrate?
Inhibition of phosphodiasterase 5 (PDE 5) resulting in smooth muscle relaxation.
74
What can the observation of side effects lead to?
a novel agent that my further lead to novel series of compounds with new therapeutic uses.
75
What are examples of new drugs found by observation of side effects?
```
Phenothiazine class of antipsychotics
Sildenafil Citrate (Viagra)
```
76
What occurred when studying antihistaminergic action of benzodioxanes?
When a phenyl substituted ethanolamines demonstrated significant antihistaminergic activity. Led to the development of antihistamines, Diphenhydramine and Ethylenediamine.
77
What did a ehtylenediamine modification lead to?
Incorporation of the aromatic rings and fusion led to tricyclic phenothiazine molecules (like promethazine).
78
Chlordiazepoxide was made form the rearrangement of what compound?
Quinazolone-3-oxides
79
Aspirin inhibits what?
Inhibition of cyclooxygenase (COX) by acetylating Ser-530 of COX-1 and Ser-516 of COX-2
80
When is random screening valuable?
When there is an absence of known drug/leads with desired activity.
81
What drugs were discovered by random screening?
Prontosil (a red colored azo dye) Inactive in vitro but active in vivo (prodrug).
82
What drugs were discovered with the help of computers and rational drug design?
zanamivir and Oseltamivir from the transition state Oxonium
83
What do Zanamivir and Oseltamivir inhibit?
Neuraminidase - an enzyme found in influenza virus
84
What is neuraminidase and what does it do?
an enzyme found in influenza virus and it cleaves glycosidic bonds between terminal Sialic acid residues and adjacent sugars. This causes viral aggregation or inappropriate binding which interferes with the infection.
85
How are Zanamivir(Relenza) and Oseltamivir(Tamiflul) administered?
Zanamivir - nasal
| Oseltamivir - Prodrug (Orally)
86
What is the chemical class of Zanamivir and Oseltamivir?
Cyclohexene-1-carboxylic acid/ethyl ester
87
What is the therapeutic class of Zanamivir and Oseltamivir?
Anti-Viral
88
What is the therapeutic uses for Zanamivir and Oseltamivir?
Prophylaxis and treatment of seasonal and non-seasonal influenza.
89
What drugs were found by studying the metabolites of known compounds?
Sulfanilamide and fexofenadine
90
Prontosil is metabolically converted to what drug?
p-aminobenzene sulfonamide (sulfanilamide)
91
What functional group differs between p-aminobenzene sulfonamide(pABA) and sulfanilamide?
the carboxyl of PABA and the sulfonamide moiety of sulfanilamide.
92
The further study of phenothiazine molecules (promethazine) led to the development of?
Chlorpromazine
