Novel 3-phenylpiperidine-4-carboxamides as highly potent and orally long-acting neurokinin-1 receptor antagonists with reduced CYP3A induction.

Hybridization of the substructures from two types of tachykinin NK1 receptor antagonists 1 and 2 generated a novel series of 3-phenylpiperidine-4-carboxamide derivatives 3. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration, exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.