PHARMACOLOGICAL PROFILE OF A NOVEL SERIES OF NK1 ANTAGONISTS - IN-VITRO AND IN-VIVO POTENCY OF BENZIMIDAZOLONE DERIVATIVES

By low throughput examination of our chemical library, compound 7 was selected as a lead NK, antagonist with a K-i of 7.1 nM. Modifications of its structure led to the finding that the in vitro potency could be markedly enhanced by disubstituting the anilino phenyl ring as in com pounds 13 or 22. Human binding data correlated rather well with result s obtained with in vitro animal mice; compound 13 was the most active with ED50 of 0.001 and 0.3 mg/kg after iv and po administration respec tively. Furthermore, antagonist 71 was found to be a potent inhibitor of SP-induced bronchoconstriction in guinea-pigs with an ED50 between 0.1 and 0.03 mg/kg iv. Furthermore, upon oral administration, 71 was o bserved to be active in a model of SP-induced bronchial hypersensitivi ty in mice, with an ID50 of around 3 mg/kg.