Bolós J, Gubert S, Anglada L, Planas J M, Burgarolas C, Castelló J M, Sacristán A, Ortiz J A
Department of Medicinal Chemistry, Centro de Investigación Grupo Ferrer, Barcelona, Spain.
J Med Chem. 1996 Jul 19;39(15):2962-70. doi: 10.1021/jm950894b.
Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.
化合物1（1-苄基-3-甲基-4-[4-(4-氟苯基)-4-氧代丁基]哌嗪）是一种被鉴定为潜在非典型抗精神病药物的合成中间体，被选作药理改进的起点。从化合物1开始，进行了一系列结构变化以提高其效力和口服生物利用度。这些变化包括一系列哌嗪、乙二胺和哌啶衍生物。哌啶系列在抑制阿扑吗啡诱导的小鼠攀爬和多动方面产生了一些口服有效的化合物，这些行为模型被认为可预测抗精神病疗效。对这些结构的进一步优化导致了高效的7-[3-(1-哌啶基)丙氧基]色原酮。在大鼠中，以远高于抑制攀爬所需的剂量抑制刻板行为和诱发僵住症表明其具有非典型抗精神病药物的特征，这被认为可预测在人类中锥体外系副作用的诱导减少。
