INTERPHENYLENE 7-OXABICYCLO[2.2.1]HEPTANE OXAZOLES - HIGHLY POTENT, SELECTIVE, AND LONG-ACTING THROMBOXANE A(2)-RECEPTOR ANTAGONISTS

A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) wer e prepared and evaluated for their thromboxane (TxA2) antagonistic act ivity in vitro and duration of action in vivo. Examination of the carb oxyl side chain indicated that the interphenylene ring substitution pa ttern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, or tho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length w ere determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophil icities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond accept or on the 4-position of the oxazole ring were critical for potent acti vity. From the analogs prepared 42 {BMS-180,291: oxabicyclo[2.2.1]hept -2-yl]methyl]benzenepropanoic acid} was found to be a potent, selectiv e, and orally-active TxA2 antagonist with a long duration of action an d has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46 ,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, resp ectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showe d a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a sing le oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggreg ation ex vivo in African green monkeys for >24 h.