IC8&9

Question 1

SAR strategies

Answer 1

1) homologation
2) alkyl substitution: vinyloguing
3) ring fusion
4) ring expansion/contraction
5) chain branching
6) bioisosteric replacement
7) rigidification
8) ring variation
9) extension of structure
10) peptidomimetics
11) simplification

Question 2

approach to SAR library

Answer 2

1) analoguing
2) simplification
3) adding groups

Question 3

properties affecting binding?

Answer 3

1) logP, lipophilicity
= affects permeability
= ie branching = less soluble, require more water molecules for solvation.

2) pharmacokinetics
= (metabolism) new group less likely to be broken down (not a target) ie peptidomimetics = more stable

3) size/steric properties
= affects binding site/binding affinity = interaction with target sites (hydrogen bonding, hydrophobic interactions, etc…)
= related to correct conformation for binding, conformational mobility…
= size and hydrophobicity?
= planar, non planar?
= fused ring?

4) pKa
= tautomerism? (keto-enol)
= resonance stability of the conjugate?

5) isomerism
- cis trans, SR enantiomerism, EZ
- racemate?

Question 4

me-too drug

Answer 4

similar to the pre-existing drug but with minor modifications to the prototype

= slight changes in SE, activity, etc.

Question 5

monovalent bioisosteres

Answer 5

F, H
OH, NH
F, OH, NH, CH3 for H
SH, OH
Cl, Br, CF3

Question 6

how does aspirin exhibit activity

Answer 6

through acetylation of the OH group (esterification) in the serine chain of the cox1 enzyme.

Question 7

how does clopidogrel exhibit activity

Answer 7

through oxidation by cyp3a4 > ring opening via hydroxylation, exposing the thiol group for disulfide bond formation with cysteine in p2y12.

Question 8

how anti factor xa inhibitors exhibit activity?

Answer 8

morpholinone = hydrophobic interaction with the hydrophobic pocket

substitution of H in the phenyl ring decreases activity.

S configuration preferred.

5-chlorthiophen has better activity than 5-chlorbenzene in the hydrophobic pocket

carbonyl and amine required for hydrogen binding with target.

Question 9

phase I and phase II metabolism reactions

Answer 9

impt for prodrugs;bioprecursors and also deactivation of drugs into inactive metabolites

Phase I metabolism
oxidation (via cytochrome P450), reduction, and hydrolysis reactions (phase I reactions include hydroxylation, epoxidation, S- and N-oxidation, dealkylation, deamination, dehalogenation, and dehydrogenation)

phase I reactions convert a parent drug to more polar (water soluble) active metabolites by unmasking or inserting a polar functional group (-OH, -SH, -NH2)

Phase II metabolism
glucuronidation, acetylation, and sulfation reactions
“conjugation reactions” that increase water solubility of drug with a polar moiety

phase II reactions convert a parent drug to more polar (water soluble) inactive metabolites by conjugation of subgroups to -OH, -SH, -NH2 functional groups on drug

Question 10

similaries in alkene and amide functional groups?

Answer 10

planarity
due to sp2 hybridised atoms.
- flat

Question 11

relation of first-pass effect on drug efficacy and activity?

Answer 11

first pass metabolism allows for more conversion into the active drug = increased activity

intestine > liver via hepatic portal vein.

Question 12

phase 2 reactions and the functional groups involved

Answer 12

glucuronidation = OH in phenol, alcohol, carboxylic acid (also thiol, amine)

sulfation = OH in phenol, alcohol

acetylation = amines

methylation = phenols, amines

glutathione conjugation = electrophilic centres

Question 13

what kind of prodrug is clopidogrel

Answer 13

bioprecursor prodrug
- not a carrier linked prodrug.
- is metabolised into its active form