New Chemistry ch5

What are the essential pharmacophoric features of 1st generation H1 antihistamines?

Two aromatic rings + central atom X + spacer 2-3 carbons + tertiary aliphatic amine

What can the central atom X be in 1st generation antihistamines?

Carbon Oxygen or Nitrogen

What is the optimal spacer length between X and amine?

2-3 carbons

What type of amine gives optimal H1 activity?

Tertiary aliphatic amine

What happens if the amine is substituted with small alkyl groups?

Maintains optimal antihistaminic activity

Which antihistamine class contains oxygen as central atom?

Ethanolamines

Which antihistamine class contains nitrogen as central atom?

Ethylenediamines

Which antihistamine class contains carbon as central atom?

Propylamines

What is formed when aromatic rings become fused into a tricyclic system?

Phenothiazine derivatives

What is formed when ethylenediamine chain is cyclized?

Piperazine derivatives

SAR: What is the effect of making structural analogs of diphenhydramine?

Less toxicity than parent diphenhydramine

SAR: What modification differentiates clemastine from diphenhydramine?

Addition of one carbon atom between oxygen and aromatic ring

SAR: Effect of adding one carbon atom in clemastine?

Maintains strong H1 activity and improves profile

SAR: Effect of incorporating basic nitrogen into a ring in clemastine?

Lower sedative effect

SAR: Which clemastine enantiomer is more potent?

RR enantiomer

SAR: Why is RR clemastine more potent?

Preferred stereochemical interaction with H1 receptor

SAR: Effect of replacing oxygen with sulfur in diphenhydramine?

Decreases antihistaminic potency

SAR: O → S replacement in ethanolamines causes what?

Loss of potency

Why is phenbenzamine highly toxic?

Contains two unsubstituted phenyl rings

Major SAR problem in phenbenzamine?

Two unsubstituted phenyl rings increase toxicity

Why does mepyramine cause drowsiness?

Rapid penetration across BBB

Why does mepyramine have anticholinergic effects?

First generation structure readily enters CNS

SAR: Why is chlorpheniramine more potent than pheniramine?

Para chloro substitution on phenyl ring

SAR: Potency increase after para chloro substitution in pheniramine?

About 20-fold increase

SAR: Effect of para chloro group on toxicity?

Decreases toxicity

SAR: Which is more potent pheniramine or chlorpheniramine?

Chlorpheniramine

SAR: What does para halogen substitution generally do in propylamines?

Increases potency

SAR: Are antihistamines stereospecific?

Yes

SAR: What happens when central atom X is replaced by carbon?

Creates a chiral center

SAR: What is the benefit of chiral center formation?

Stereoselective H1 receptor binding

SAR: Which pheniramine configuration has higher H1 affinity?

S configuration

SAR: Which chlorpheniramine optical isomer is more potent?

Dextrorotatory isomer

SAR: Which chlorpheniramine optical isomer is less potent?

Levorotatory isomer

SAR: Why is dextrorotatory chlorpheniramine more potent?

Better stereoselective receptor interaction

SAR: What is the optimal terminal nitrogen for propylamines?

Tertiary amine

SAR: Effect of converting tertiary amine to secondary or primary amine?

Reduced activity

SAR: Why is tertiary amine preferred?

Provides maximal receptor binding

SAR: Which class has longer duration ethanolamines or alkylamines?

Alkylamines

SAR: Which class has less sedation ethanolamines or alkylamines?

Alkylamines

SAR: Effect of increasing branching in alkylamine side chain?

Decreases potency

SAR: Effect of substitution between chiral carbon and nitrogen?

Decreases potency

SAR: Effect of excessive branching on metabolism?

Alters metabolism and decreases activity

SAR: Effect of excessive branching on toxicity?

Changes toxicity profile

What structural modification converts ethylenediamines to piperazines?

Incorporation of both nitrogens into a piperazine ring

Advantage of piperazine derivatives?

Retain H1 activity with modified pharmacokinetics

Which H2 antagonist contains an imidazole ring?

Cimetidine

Which H2 antagonist contains a furan ring?

Ranitidine

Which H2 antagonist contains a thiazole ring?

Famotidine

SAR of H2 antagonists: Is imidazole essential?

No

SAR: Effect of replacing imidazole with furan?

Enhances activity

SAR: Effect of replacing imidazole with thiazole?

Enhances activity

SAR: Which heterocycle is present in ranitidine?

Furan

SAR: Which heterocycle is present in famotidine?

Thiazole

SAR: Optimal distance between heterocyclic ring and terminal nitrogen?

Four atoms

SAR: Why should ring and terminal nitrogen be separated by four atoms?

Provides optimal H2 receptor binding

SAR: Effect of shortening or lengthening beyond four atoms?

Reduced activity

SAR: Effect of isosteric thioether linkage?

Enhances activity

SAR: Why is thioether linkage important?

Improves antagonist potency

SAR: What type of substituents are required for maximal H2 antagonism?

Polar non-basic substituents

SAR: Effect of adding polar non-basic substituents?

Increases antagonist activity

Which H2 antagonist inhibits CYP450 strongly?

Cimetidine

SAR/Clinical: What problem results from CYP450 inhibition by cimetidine?

Many drug interactions

Which H2 antagonist has only 10 percent of cimetidine CYP450 affinity?

Ranitidine

Clinical advantage of ranitidine over cimetidine?

Fewer drug interactions

Potency of ranitidine compared with cimetidine?

10 times more potent

Which H2 antagonist has no significant CYP450 inhibition?

Famotidine

Potency of famotidine compared with cimetidine?

30 times more potent

Rank H2 antagonists by potency.

Famotidine > Ranitidine > Cimetidine

Rank H2 antagonists by CYP450 inhibition.

Cimetidine > Ranitidine > Famotidine

What structural trend improves H2 antagonist activity?

Replace imidazole with other heterocycles plus maintain four atom spacer plus thioether linkage

SAR summary for ethanolamines?

Extra carbon and ring nitrogen decrease sedation RR enantiomer increases potency O→S decreases potency

SAR summary for propylamines?

Para chloro increases potency S configuration preferred dextrorotatory isomer stronger tertiary amine required

SAR summary for H2 antagonists?

Imidazole not essential furan/thiazole increase activity four atom separation optimal thioether enhances activity polar nonbasic groups required