Shishido, Yuji, Wakabayashi, Hiroaki, Koike, Hiroki, Ueno, Naomi, Nukui, Seiji, Yamagishi, Tatsuya, Murata, Yoshinori, Naganeo, Fumiharu, Mizutani, Mayumi, Shimada, Kaoru, Fujiwara, Yoshiko, Sakakibara, Ayano, Suga, Osamu, Kusano, Rinko, Ueda, Satoko, Kanai, Yoshihito, Tsuchiya, Megumi, and Satake, Kunio
Abstract: A novel central nervous system (CNS) selective neurokinin-1 (NK1) 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 =0.2nM) for the human NK1 receptor in IM-9 cells, potent activity in the [Sar9, Met(O2)11]SP-induced gerbil tapping model (ED50 =0.04mg/kg, sc) and in the ferret cisplatin (10mg/kg, ip)-induced anti-emetic activity model (vomiting: ED90 =0.07mg/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. [Copyright &y& Elsevier]