Carpenter Joseph, Wang Ying, Wu Gang, Feng Jianxin, Ye Xiang-Yang, Morales Christian L, Broekema Matthias, Rossi Karen A, Miller Keith J, Murphy Brian J, Wu Ginger, Malmstrom Sarah E, Azzara Anthony V, Sher Philip M, Fevig John M, Alt Andrew, Bertekap Robert L, Cullen Mary Jane, Harper Timothy M, Foster Kimberly, Luk Emily, Xiang Qian, Grubb Mary F, Robl Jeffrey A, Wacker Dean A
Departments of Discovery Chemistry, Discovery Biology, Lead Evaluation, Computer-Assisted Drug Design, Discovery Toxicology, and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
J Med Chem. 2017 Jul 27;60(14):6166-6190. doi: 10.1021/acs.jmedchem.7b00385. Epub 2017 Jul 7.
Agonism of the 5-HT receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT and 5-HT receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT with high selectivity over the related 5-HT and 5-HT receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT antagonist.
5-羟色胺（5-HT）受体激动是药理减肥研究最深入且临床已证实的机制之一。对密切相关的5-HT和5-HT受体具有选择性至关重要，因为已表明激活这些受体会导致不良副作用和重大安全问题。在本通讯中，我们报告了一种新的筛选模式的开发，该模式利用活性位点突变体D134A（D3.32）5-HT受体来鉴定非典型激动剂结构。我们还报告了一类新型5-HT非碱性杂环酰胺激动剂的发现和优化。围绕筛选命中物进行的构效关系（SAR）研究提供了一系列在5-HT上具有强效的激动剂，对相关的5-HT和5-HT受体亚型具有高选择性。通过用各种五元及六元杂环取代酰胺进行进一步优化，得到了6-(1-乙基-3-(喹啉-8-基)-1H-吡唑-5-基)哒嗪-3-胺（69）。在自由采食模型中，给大鼠口服69可减少食物摄入量，这可被选择性5-HT拮抗剂完全逆转。
