Bhagwat S S, Gude C, Boswell C, Contardo N, Cohen D S, Dotson R, Mathis J, Lee W, Furness P, Zoganas H
Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
J Med Chem. 1992 Nov 13;35(23):4373-83. doi: 10.1021/jm00101a015.
The title compound (10a) and its analogs were synthesized and found to possess two activities, the inhibition of the biosynthesis of thromboxane A2 and antagonism of its receptors. The in vitro and in vivo profile of these compounds as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) is described. 10a and its analogs displayed very potent TxRA activity in human washed platelets (IC50 approximately 10(-7)-10(-9) M) and dog saphenous vein (pA2 approximately 9) and also potent TxSI activity (IC50 approximately 10(-9) M). The good bioavailability and the long duration of action of some of these compounds was demonstrated using ex vivo measurement of the TxRA activity upon oral administration to guinea pigs. Compounds 10a, 20, and 33 potently inhibited arachidonic acid induced bronchoconstriction in guinea pigs.
