title: Novel 3-phenylpiperidine-4-carboxamides as highly potent and orally long-acting neurokinin-1 receptor antagonists with reduced CYP3A induction.
abstract: The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. 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. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Shirai_Junya@takeda.co.jp
authors.forename: Junya
authors.initials: J
authors.lastname: Shirai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Morimoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Maezaki
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.forename: Izumi
authors.initials: I
authors.lastname: Kamo
authors.forename: Shiho
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishigami
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikeura
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C572009:1-(amino(oxo)acetyl)-N-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide; D000577:Amides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D000077297:Pregnane X Receptor; D018040:Receptors, Neurokinin-1; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A