新規セロトニン(5-HT_3)受容体拮抗剤・塩酸ラモセトロンの創薬化学研究にて

概要

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Design, synthesis and pharmacophore modeling is described, on the basis of a medicinal chemistry research for a discovery of ramosetron hydrochloride as a novel serotonine (5-HT3) receptor antagonist, which has been launched as an effective agent for the treatment of nausea and vomiting associated with cancer chemotherapy. Exploiting a new lead generation, a tetrahydrobenzimidazole derivative 11 was found from a various kind of fused imidazole derivatives. Optimization of compound 11 as racemates, followed by optical resolution, was accomplished to discover ramosetron as a potent, selective and optical active 5-HT3 receptor antagonist. Three-dimensional molecular modeling studies, based on a structure activity relationships, suggested that chiral selection might be related to the conformationally restricted tetrahydrobenzimidazole ring, and a new pharmacophore model for the 5-HT3receptor antagonist was proposed. Further, preparation of a chiral degradation product as well as a metabolite of ramosetron was also achieved.
社団法人有機合成化学協会の論文
2001-02-01