title: Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'.
abstract: A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan. yuji.shishido@raqualia.com
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shishido
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Koike
authors.forename: Naomi
authors.initials: N
authors.lastname: Ueno
authors.forename: Seiji
authors.initials: S
authors.lastname: Nukui
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamagishi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murata
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Naganeo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mizutani
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Ayano
authors.initials: A
authors.lastname: Sakakibara
authors.forename: Osamu
authors.initials: O
authors.lastname: Suga
authors.forename: Rinko
authors.initials: R
authors.lastname: Kusano
authors.forename: Satoko
authors.initials: S
authors.lastname: Ueda
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kanai
authors.forename: Megumi
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Kunio
authors.initials: K
authors.lastname: Satake
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D005849:Gerbillinae; D006801:Humans; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
chemical_list: C532759:3-(6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl)methylamino-2-phenylpiperidine; D000932:Antiemetics; D001578:Benzopyrans; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D002945:Cisplatin