DESIGN OF NEW POTENTIAL 5-LIPOXYGENASE INHIBITORS, DUAL THROMBOXANE SYNTHASE INHIBITORS, AND THROMBOXANE A(2) RECEPTOR ANTAGONISTS BY AM1

Leukotrienes and thromboxane A(2) are autacoids derived from arachidon ic acid (5,8,11,14-icosatretraenoic acid). They are synthesized in cel ls by 5-lipoxygenase and thromboxane synthase, respectively. Leukotrie nes are related to inflammatory and allergic diseases, while thromboxa ne A(2) is a potent platelet aggregating and vasoconstrictor agent inv olved in cardiovascular pathologies. In this article we have calculate d partial potential energy surfaces at the AM1 level for some 5-lipoxy genase inhibitors,thromboxane synthase inhibitors, thromboxane A(2) re ceptor antagonists, and a dual blocker which inhibits thromboxane synt hase and antagonizes thromboxane A(2) receptor. Our objective was to i dentify stereoelectronic properties and topographical requirements for these compounds that could be related to their biological activities. Based on our results and on molecular mechanisms of pharmacological a ction, we were able to propose new potential 5-lipoxygenase inhibitors and dual blockers derived from pyrazole, pyrrole, 1,2,3-triazole, and 1,2,4-triazole. (C) 1995 John Wiley & Sons, Inc.