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 arachidonic acid (5,8,11,14-icosatretraenoic acid). They are synthesized in cells by 5-lipoxygenase and thromboxane synthase, respectively. Leukotrienes are related to inflammatory and allergic diseases, while thromboxane A(2) is a potent platelet aggregating and vasoconstrictor agent involved in cardiovascular pathologies. In this article we have calculated partial potential energy surfaces at the AM1 level for some 5-lipoxygenase inhibitors,thromboxane synthase inhibitors, thromboxane A(2) receptor antagonists, and a dual blocker which inhibits thromboxane synthase and antagonizes thromboxane A(2) receptor. Our objective was to identify 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 action, 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.