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Structure-activity studies on triazolothienodiazepine derivatives as platelet-activating factor antagonists
S Miyazawa1, K Okano, N Shimomura
1Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Chemical & Pharmaceutical Bulletin
|December 1, 1991
Summary
Researchers developed novel triazolodiazepines to inhibit platelet activating factor (PAF). The study found that specific (+)-isomers exhibit significantly higher anti-PAF potency, leading to the selection of E6123 for clinical trials.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- Platelet activating factor (PAF) is implicated in various inflammatory and allergic conditions.
- Developing effective inhibitors of PAF is a key therapeutic goal.
Purpose of the Study:
- To synthesize and evaluate novel triazolodiazepine derivatives for anti-platelet activating factor (PAF) activity.
- To identify potent and safe drug candidates for clinical investigation.
Main Methods:
- Synthesis of a series of triazolodiazepine compounds.
- Structure-activity relationship (SAR) analysis to optimize anti-PAF activity.
- Chiral separation of enantiomers using optical resolving columns.
- In vitro anti-PAF assays and pharmacokinetic/toxicology evaluations.
Main Results:
- SAR studies indicated that methyl group substitution at the 8-position of the thienodiazepine nucleus enhances activity duration.
- Separated enantiomers showed significant differences in potency; (+)-isomers were 50-200 times more potent than (-)-isomers.
- Compound E6123 ((+)-isomer) demonstrated favorable toxicology and pharmacokinetic profiles.
Conclusions:
- The synthesized triazolodiazepines, particularly E6123, show promising anti-PAF activity.
- Stereochemistry plays a crucial role in the anti-PAF potency of these compounds.
- E6123 is a strong candidate for further clinical development as an anti-PAF agent.