Structure-activity relationships of arylimidazopyridine cardiotonics: discovery and inotropic activity of 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]pyridine

Abstract

Recently, several noncatecholamine, nonglycoside cardiotonic drugs were discovered that possess both inotropic and vasodilator activities in experimental animals [cats and dogs] and man. Prototypical compounds include amrinone, sulmazole, and fenoximone. The structural requirements necessary for optimal inotropic activity in a series of molecules containing a heterocyclic ring fused to 2-phenylimidazole were investigated; and 2-phenylimidazo[4,5-c]pyridines were generally 5- to 10-fold more potent than analogous 2-phenylimidazo[4,5-b]pyridines (e.g., sulmazole) or 8-phenylpurines. All imidazo[4,5-c]pyridine analogs tested were orally active; only one of the imidazo[4,5-b]pyridine derivatives, sulmazole, was significantly active. One of several highly active compounds in the [4,5-c] series was LY175326 (2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-8-imidazo[4,5-c]pyridine hydrochloride). The structure-activity relationship of this series is presented and compared to that of the imidazo[4,5-b]pyridine and purine series.