title: Design, structure-activity relationship, and highly efficient asymmetric synthesis of 3-phenyl-4-benzylaminopiperidine derivatives as novel neurokinin-1 receptor antagonists.
abstract: We synthesized a series of novel 3-phenyl-4-benzylaminopiperidine derivatives that were identified as potent tachykinin NK(1) receptor antagonists by structural modification of the 3-benzhydrylpiperidone derivative through high-throughput screening. N-{2-[(3R,4S)-4-({2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}amino)-3-phenyl-1-piperidinyl]-2-oxoethyl}acetamide ((+)-39) was found to be one of the most potent tachykinin NK(1) receptor antagonists with high metabolic stability. Highly efficient asymmetric synthesis of (+)-39 was achieved via dynamic kinetic resolution.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Shirai_Junya@takeda.co.jp
authors.forename: Junya
authors.initials: J
authors.lastname: Shirai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Izumi
authors.initials: I
authors.lastname: Kamo
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikeura
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines