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, Satake Kunio
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan.
Bioorg Med Chem. 2008 Aug 1;16(15):7193-205. doi: 10.1016/j.bmc.2008.06.047. Epub 2008 Jun 26.
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.
一种新型的中枢神经系统（CNS）选择性神经激肽-1（NK(1)）受体拮抗剂，(2S,3S)-3-[(1R)-6-甲氧基-1-甲基-1-三氟甲基异苯并二氢吡喃-7-基]-甲基氨基-2-苯基哌啶“CJ-17,493”（化合物(+)-1），通过以脂肪酶-PS进行动力学拆分作为关键步骤立体选择性地合成。化合物(+)-1在IM-9细胞中对人NK(1)受体表现出高选择性亲和力（K(i)=0.2 nM），在[Sar(9), Met(O(2))(11)]SP诱导的沙鼠轻敲模型（ED(50)=0.04 mg/kg，皮下注射）和雪貂顺铂（10mg/kg，腹腔注射）诱导的抗呕吐活性模型（呕吐：ED(90)=0.07 mg/kg，皮下注射）中具有强效活性，所有活性水平与CP-122,721相当。此外，化合物(+)-1表现出线性药代动力学，而非CP-122,721的超剂量比例关系，这一结果为CP-122,721所观察到的临床问题提供了一个潜在的解决方案。
