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'.
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DOI：
10.1016/j.bmc.2008.06.047
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发表时间：
2008-08
影响因子：
3.5
通讯作者：
Y. Shishido;Hiroaki Wakabayashi;Hiroki Koike;Naomi Ueno;S. Nukui;T. Yamagishi;Y. Murata;F. Naganeo-F
中科院分区：
文献类型：
--
作者：
Y. Shishido;Hiroaki Wakabayashi;Hiroki Koike;Naomi Ueno;S. Nukui;T. Yamagishi;Y. Murata;F. Naganeo-F
以脂肪酶-PS动力学拆分为关键步骤，立体选择性地合成了一种新的中枢神经系统选择性神经激肽-1受体拮抗剂(2S，3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine‘CJ-17,493’(化合物(+)-1)。化合物(+)-1在IM-9细胞中对人NK1受体表现出较高的选择性亲和力(Ki=0.2 nM)，在[Sar9，Met(O2)11]SP诱导的沙土鼠敲打模型(ED50=0.04 mg/kg，sc)和雪貂顺铂(10 mg/kg，ip)诱导的止吐作用模型(ED90=0.07 mg/kg，sc)中显示出较强的活性，所有活性水平均与CP-122,721相当。此外，化合物(+)-1呈现线性药代动力学，而不是CP-122,721的超剂量比例，这一结果为CP-122,721的临床问题提供了潜在的解决方案。
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 (Ki=0.2nM) for the human NK1receptor 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.