A novel series of selective leukotriene antagonists: exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles

A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most pot...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-09, Vol.33 (9), p.2437-2451
Main Authors: Yee, Ying K, Bernstein, Peter R, Adams, Edward J, Brown, Frederick J, Cronk, Laura A, Hebbel, Kevin C, Vacek, Edward P, Krell, Robert D, Snyder, David W
Format: Article
Language:English
Subjects:
Animals
Bronchodilator Agents - chemical synthesis
Bronchodilator Agents - pharmacology
Chemical Phenomena
Chemistry
Guinea Pigs
In Vitro Techniques
Indazoles - chemical synthesis
Indazoles - pharmacology
Indoles - chemical synthesis
Indoles - pharmacology
Leukotriene Antagonists
Muscle, Smooth - drug effects
Pyrazoles - chemical synthesis
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - pharmacology
Trachea - drug effects
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Summary:A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most potent carboxylic acids 1, tetrazoles 20, and aryl sulfonimides 21. The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids 1. The o-tolyl sulfonimides such as 114 show greater oral potency than the phenyl sulfonimides at a given level of in vitro activity. Acidic keto sulfone derivatives 10 (Nu = CH-(CO2CH3)SO2Ph) mimic the activity of the sulfonimides.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00171a018