Du Wu, Jewell James P, Lin Linus S, Colandrea Vincent J, Xiao Jing C, Lao Julie, Shen Chun-Pyn, Bateman Thomas J, Reddy Vijay B G, Ha Sookhee N, Shah Shrenik K, Fong Tung M, Hale Jeffrey J, Hagmann William K
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5195-9. doi: 10.1016/j.bmcl.2009.07.046. Epub 2009 Jul 24.
Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd generation of CB1R inverse agonist from the acyclic amide scaffold. We replaced the oxygen linker in taranabant with nitrogen and prepared a series of amino heterocyclic analogs through a divergent synthesis. Although in general, the amine linker gave reduced binding affinity, potent and selective CB1R inverse agonist was identified from the amino heterocycle series. Molecular modeling was applied to study the binding of the amino heterocycle series at CB1 binding site. The in vitro metabolism of representative members was studied and only trace glucuronidation was found. Thus, it suggests that the right hand side of the molecule may not be the appropriate site for glucuronidation.
肥胖是一种影响全球大量人口的慢性疾病。CB1作为肥胖治疗靶点一直受到深入研究。替拉那班由默克公司发现并开发，是第一代CB1R反向激动剂。本文报道了我们从无环酰胺骨架开发第二代CB1R反向激动剂的部分工作。我们用氮取代了替拉那班中的氧连接基，并通过发散合成制备了一系列氨基杂环类似物。虽然一般来说，胺连接基降低了结合亲和力，但从氨基杂环系列中鉴定出了强效且选择性的CB1R反向激动剂。应用分子建模研究氨基杂环系列在CB1结合位点的结合情况。研究了代表性成员的体外代谢，仅发现微量的葡萄糖醛酸化。因此，这表明分子的右侧可能不是葡萄糖醛酸化的合适位点。
