Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'.
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.
Shishido
Yuji
Y
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan. yuji.shishido@raqualia.com
Wakabayashi
Hiroaki
H
Koike
Hiroki
H
Ueno
Naomi
N
Nukui
Seiji
S
Yamagishi
Tatsuya
T
Murata
Yoshinori
Y
Naganeo
Fumiharu
F
Mizutani
Mayumi
M
Shimada
Kaoru
K
Fujiwara
Yoshiko
Y
Sakakibara
Ayano
A
Suga
Osamu
O
Kusano
Rinko
R
Ueda
Satoko
S
Kanai
Yoshihito
Y
Tsuchiya
Megumi
M
Satake
Kunio
K
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
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