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, (2 S,3 S)-3-[(1 R)-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, sc) and in the ferret cisplatin (10 mg/kg, ip)-induced anti-emetic activity model (vomiting: ED 90 = 0.07 mg/kg, sc), 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.