Design, Synthesis, and SAR Study of a Series of N-Alkyl-N'-[2-(aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine as Selective Antagonists of the TP alpha and TP beta Isoforms of the Human Thromboxane A sub(2) Receptor

The prostanoid thromboxane (TX)A sub(2) exerts its proaggregant and constrictive actions upon binding to the specific TXA sub(2) receptor (TP), a member of the G-protein coupled receptor superfamily. In humans, TXA sub(2) signals through two distinct TP isoforms, TP alpha and TP beta . Herein, we describe the design, synthesis, and SAR study of a series of original N-alkyl-N'-[2-(aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine. The SAR study was based on the results of a functional assay, TP-mediated intracellular calcium ([Ca super(2+)] sub(i)) mobilization performed on the two separate isoforms. Optimal nature and position of several structural moieties was defined for both activity and selectivity toward TP alpha and TP beta isoforms. Three compounds (9h, 9af, and 9ag), showing increased selectivity for TPssp relative to TP alpha (23.2:1, 18.1:1, 19.9:1, respectively), were selected for further experiments, and their activity was confirmed in a platelet aggregation assay. This study represents the first extended SAR study dealing with the identification of isoform selective antagonists for the human TXA sub(2) receptor.