NONPROSTANOID PROSTACYCLIN MIMETICS .5. STRUCTURE-ACTIVITY-RELATIONSHIPS ASSOCIATED WITH 4,5-DIPHENYL-2-OXAZOLYL)-5-OXAZOLYL]PHENOXY]ACETICACID

[2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phenoxy]acetic acid (3) was previo usly identified as a nonprostanoid prostacyclin (PGI(2)) mimetic that potently inhibits ADP-induced aggregation of human platelets with an I C50 of 0.18 mu M. As part of an effort to further explore structure-ac tivity relationships for this class of platelet inhibitor and to provi de additional insight into the nonprostanoid PGI(2) mimetic pharmacoph ore, the effect of constraining the cis-olefin moiety of 3 into variou s ring systems was examined. Incorporation of the cis-olefin of 3 into either an oxazole (26) or an unsubstituted pyrazole (35) heterocycle provided compounds that are equipotent with progenitor 3. However, the oxazole 11f, which is isomeric with 26, inhibits ADP-induced human pl atelet aggregation in vitro with an IC50 of 0.027 mu M, 6-fold more po tent than 3, 26, or 35. These results suggest that the central oxazole ring of 11f is functioning as more than a simple scaffold that provid es optimal stereodefinition for interaction with the PGI(2) receptor. The nitrogen atom of the central heterocycle of 11f is postulated to e ngage in hydrogen-bond formation with a donor moiety in the PGI(2) rec eptor protein, an interaction not available to 26 due to the markedly different topology. In support of this contention, the crystal structu res of 11f and 26 contain strong intermolecular hydrogen bonds between the carboxylic acid hydrogen atom and the nitrogen atom of the centra l oxazole ring. Although 11f and 26 are exact isosteres and could, in principle, adopt the same molecular packing arrangement in the solid s tate, this is not the case, and the intermolecular hydrogen-bonding in teractions in 11f and 26 are accommodated by entirely different molecu lar packing arrangements. Incorporation of the olefin moiety of 3 into a benzene ring provided a compound, 40, over 60-fold weaker with an I C50 of 11.1 mu M. The affinities of 11f, 26, 31, 32, and 40 for the hu man platelet PGI(2) receptor, determined by displacement of [H-3]ilopr ost, correlated with inhibition of platelet function. The solid-state structures of 11f, 26, 31, 32, and 40 were determined and revealed tha t the more potent compounds 11f and 26 adopt a relatively planar overa ll topography. In contrast, the central phenyl ring and the phenoxy ri ng of the weakly active compound 40 are rotated by 53 degrees from pla narity. The chemical shifts of the protons of the phenoxy rings of 3, 11f, 18, 26, 31, 32, and 40 suggest that in solution 3, 11f, 18, and 2 6 adopt a planar conformation while 40 does not. Taken together, these data suggest that the more potent nonprostanoid PGI(2) mimetics are t hose in which elements of the side chain are able to adopt a relativel y planar topographical arrangement.