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PF-00217830 的发现:芳基哌嗪萘啶酮类作为精神分裂症和双相情感障碍的 D2 部分激动剂。

Discovery of PF-00217830: aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder.

机构信息

Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.

出版信息

Bioorg Med Chem Lett. 2011 May 1;21(9):2621-5. doi: 10.1016/j.bmcl.2011.01.059. Epub 2011 Jan 22.

DOI:10.1016/j.bmcl.2011.01.059
PMID:21353774
Abstract

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D(2) partial agonists is described. Our goal was to optimize the affinities for the D(2), 5-HT(2A) and 5-HT(1A) receptors, such that the D(2)/5-HT(2A) ratio was greater than 5 to ensure maximal occupancy of these receptors when the D(2) occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED=0.3mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).

摘要

描述了一系列新型芳基哌嗪萘啶酮 D(2) 部分激动剂的合成和构效关系(SAR)。我们的目标是优化对 D(2)、5-HT(2A) 和 5-HT(1A) 受体的亲和力,使得 D(2)/5-HT(2A) 比值大于 5,以确保当 D(2) 占有率达到有效水平时,这些受体的占有率最大化。这一策略导致了 PF-00217830(2)的鉴定,它对 sLMA(MED=0.3mg/kg)和 DOI 诱导的大鼠头部抽搐具有强大的抑制作用(在 0.3 和 1mg/kg 时分别为 31%和 78%),在最高测试剂量(10mg/kg)时没有观察到僵住。

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