2. Academic Validation
  3. Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'

Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'

  • Bioorg Med Chem. 2008 Aug 1;16(15):7193-205. doi: 10.1016/j.bmc.2008.06.047.
Yuji Shishido 1,  Hiroaki Wakabayashi,  Hiroki Koike,  Naomi Ueno,  Seiji Nukui,  Tatsuya Yamagishi,  Yoshinori Murata,  Fumiharu Naganeo,  Mayumi Mizutani,  Kaoru Shimada,  Yoshiko Fujiwara,  Ayano Sakakibara,  Osamu Suga,  Rinko Kusano,  Satoko Ueda,  Yoshihito Kanai,  Megumi Tsuchiya,  Kunio Satake
Affiliations

Affiliation

  • 1 Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan. [email protected]
PMID: 18640044 DOI: 10.1016/j.bmc.2008.06.047
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.

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