SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL BENZIMIDAZOLEAND IMIDAZO[4,5-B]PYRIDINE ACID-DERIVATIVES AS THROMBOXANE-A(2) RECEPTOR ANTAGONISTS

A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine s ubstituted in the 2-position by an alkanoic or mercaptoalkanoic acid c hain was synthesized for evaluation as potential thromboxane A2/prosta glandin H-2 (TXA2/PGH2) receptor antagonists. The affinity of each com pound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [I-125]PTA-OH. Structure-activity re lationships led to the conclusions that 2-alkanoic acid derivatives we re slightly more potent than 2-mercaptoalkanoic acids and that compoun ds possessing a 3,3-dimethylbutanoic acid in the 2-position were defin itely the most potent with K(i) values of 4-39 nM (11a, 11g-x, 37a, 37 f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side ch ain by a shorter one led to a marked decrease of affinity (11b and 11c ; K(i) = 5600 and 1700 nM, respectively). Compounds of benzimidazole a nd imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have K(i) values of 6 and 7 nM, respectively). The interesting pha rmacological profile of compound 23a (UP 116-77: -oimidazo[4,5-b]pyrid in-2-yl]-3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.