Pharmacological profile of a novel series of NK1, antagonists. In vitro and in vivo potency of benzimidazolone derivatives

Article abstract of DOI:10.1016/S0223-5234(97)82771-7

By low throughput examination of our chemical library, compound 7 was selected as a lead NK₁, 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 compounds 13 or 22. Human binding data correlated rather well with results obtained with in vitro animal smooth muscle preparations. Several agents proved to possess antinociceptive properties as exemplified in the hot-plate test in mice; compound 13 was the most active with ED₅₀ of 0.001 and 0.3 mg/kg after iv and po administration respectively. 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 observed to be active in a model of SP-induced bronchial hypersensitivity in mice, with an ID₅₀ of around 3 mg/kg.