Design of an antithrombotic-antihypertensive agent (Wy 27569). Synthesis and evaluation of a series of 2-heteroaryl-substituted dihydropyridines

Article abstract of DOI:10.1021/jm00164a028

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA₂ synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl) -6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA₂ synthetase in rabbit and human platelets in vitro and reduced plasma TXB₂ levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF(1α), reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.