Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity |
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| Authors: | He Shuwen Ye Zhixiong Dobbelaar Peter H Bakshi Raman K Hong Qingmei Dellureficio James P Sebhat Iyassu K Guo Liangqin Liu Jian Jian Tianying Lai Yingjie Franklin Christopher L Reibarkh Mikhail Holmes Mark A Weinberg David H MacNeil Tanya Tang Rui Tamvakopoulos Constantin Peng Qianping Miller Randy R Stearns Ralph A Chen Howard Y Chen Airu S Strack Alison M Fong Tung M Wyvratt Matthew J Nargund Ravi P |
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| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. shuwen_he@merck.com |
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| Abstract: | We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models. |
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