Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors

• Published in: Journal of medicinal chemistry Vol. 30; no. 9; pp. 1588 - 1595
• Main Authors: Manley, Paul W., Allanson, Nigel M., Booth, Robert F. G., Buckle, Philip E., Kuzniar, Edward J., Lad, Nagin, Lai, Steve M. F., Lunt, David O., Tuffin, David P.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1987
• Subjects: Animals; Blood Platelets - drug effects; Blood Platelets - enzymology; Chemistry; Chromatography, High Pressure Liquid; Collagen - pharmacology; Epoprostenol - biosynthesis; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Imidazoles - pharmacology; Organic chemistry; Preparations and properties; Rabbits; Structure-Activity Relationship; Thromboxane A2 - biosynthesis; Thromboxane B2 - blood; Thromboxane-A Synthase - antagonists & inhibitors; Thromboxane synthetase; Five membered ring; Ether; Structure activity relation; Nitrogen heterocycle; Enzyme inhibitor; Benzenic compound; NMR spectrum
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00392a011

Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.