强效CB1受体拮抗剂系列的设计：外周靶向药物的潜在骨架
Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents.
作者信息
Dow Robert L, Carpino Philip A, Gautreau Denise, Hadcock John R, Iredale Philip A, Kelly-Sullivan Dawn, Lizano Jeffrey S, O'Connor Rebecca E, Schneider Steven R, Scott Dennis O, Ward Karen M
机构信息
Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
出版信息
ACS Med Chem Lett. 2012 Mar 21;3(5):397-401. doi: 10.1021/ml3000325. eCollection 2012 May 10.
Abstract
Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.
摘要
大麻素-1（CB1）受体信号传导的拮抗剂已被证明可抑制人类的进食行为，但CB1介导的中枢神经系统（CNS）副作用已导致针对该靶点的先导药物停止上市和进一步研发。然而，外周选择性CB1受体拮抗剂可能具有提供所需疗效同时降低CNS副作用的潜力。在本报告中，我们详细介绍了一种新型双环骨架（3）的发现及其构效关系分析，该骨架在临床前进食模型中表现出强大的CB1受体拮抗作用和口服活性。物理性质的优化已导致鉴定出预计具有降低的CNS暴露的类似物，这些类似物可作为设计外周靶向CB1受体拮抗剂的起点。
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