Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists

• Published in: Journal of medicinal chemistry Vol. 35; no. 7; pp. 1200 - 1209
• Main Authors: Sawyer, J. Scott, Baldwin, Ronald F, Rinkema, Lynn E, Roman, Carlos R, Fleisch, Jerome H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-04-1992
• Subjects: Animals; Chemistry; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Ileum - drug effects; Ileum - physiology; Male; Molecular Structure; Muscle Contraction - drug effects; Organic chemistry; Preparations and properties; Quinolines - chemical synthesis; Quinolines - pharmacology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - physiology; Receptors, Leukotriene; Structure-Activity Relationship; Tetrazoles - chemical synthesis; Tetrazoles - pharmacology; Five membered ring; Ether; Structure activity relation; Nitrogen heterocycle; Bicyclic compound; Aromatic compound; Leukotriene D4; Antagonist; In vitro; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00085a005

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum. Compound 32, LY287192 (2-[[5-[3-[2-(7-chloroquinolin-2- yl)ethenyl]phenyl]-2H-tetrazol-2-yl]methyl]-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1 +/- 0.3. Qualitative structure-activity studies have demonstrated specific requirements for the best activity. In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency. In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer. This pattern was reversed when the acid was substituted at the para position. The quinoline unit may be replaced by other nitrogen-containing heterocycles.