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Various N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarbamoyl heterocycles (1, 2 and 3) modified at rings A and B in the isoquinolone (1a) and pyrido[3,4-b]pyridine (2a) nuclei were prepared and evaluated for NK1 receptor antagonistic activities. The structure-activity relationship studies on this series, along with conformational analysis, showed that (i) for ring A, 6-membered heterocycles are preferable to 5-membered heterocycles (a ca. 300-fold difference in potency), (ii) the 6-membered ring seems to function as an anchor by fixing the pendant phenyl group in a desirable orientation for receptor binding, and (iii) since compounds with aromatic rings (2) and those with aliphatic rings (3) as ring B both show good potency, this ring does not seem to be essential for receptor recognition. Among the compounds synthesized, the tetrahydropyridine derivatives 3a, 3b and 3f exhibited excellent inhibitory effects both in vitro and in vivo, with potent activity upon oral administration (ED50 = 0.20-0.27 mg/kg) (capsaicin-induced plasma extravasation in guinea pig trachea).

chemical and pharmaceutical bulletin/chemical and pharmaceutical bulletin

Potent NK1 Receptor Antagonists: Synthesis and Antagonistic Activity of Various Heterocycles with an N-(3,5-Bis(trifluoromethyl)benzyl)-N-methylcarbamoyl Substituent.