Inotropic activity of heterocyclic analogues of isomazole

Abstract Aryl-substituted benzimidazole, imidazopyridine, imidazopyrazine, imidazopyridazine, oxazolopyridine, purine, pyrollopyridine and thiazolopyridine derivatives have been prepared and evaluated as inotropic agents. Purine 8 and the 1 H -imidazo[4,5- c ]- and [4,5- d ]pyridazines 9 and 10 proved to be of most interest, having similar in vivo inotropic potencies to sulmazole. The p K a's, protonation sites and lipophilicities for most heterocycles were determined experimentally and some of their electronic properties calculated. For a subset of active heterocycles a correlation was observed between in vitro inotropism and the charge density of the imidazo nitrogen adjacent to the electrostatic potential minimum. Structure—activity relationships are discussed in some detail.