Non-prostanoid prostacyclin mimetics. 6. Derivatives of 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid modified beta-to the oxazole ring.

2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid, 1, has been described as a non-prostanoid PGI2 mimetic that demonstrates anti-thrombotic properties of long duration in animal models of thrombosis. The effects of substitution and modification of the carbon beta-to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP-induced human platelet aggregation in vitro. Potency was sensitive to both the size of the substituent and the identity of the beta-atom. The carbamates 13c-e demonstrated IC50's of 0.28-0.36 microM and were significantly more potent than the progenitor 1, IC50 = 1.2 microM. The ethyl carbamate 13c displaced [3H]-iloprost from platelet membranes in a concentration-dependent fashion that was half maximal at 20 nM, which compares with IC50's of 171 nM for 1 and 39 nM or unlabelled iloprost. Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for PGI2, identifying 13c as a partial agonist at the platelet PGI2 receptor.