Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity

  • Bioorg Med Chem Lett. 2010 Aug 1;20(15):4399-405. doi: 10.1016/j.bmcl.2010.06.062.
Shuwen He  1 ,  Zhixiong Ye ,  Peter H Dobbelaar ,  Iyassu K Sebhat ,  Liangqin Guo ,  Jian Liu ,  Tianying Jian ,  Yingjie Lai ,  Christopher L Franklin ,  Raman K Bakshi ,  James P Dellureficio ,  Qingmei Hong ,  David H Weinberg ,  Tanya Macneil ,  Rui Tang ,  Alison M Strack ,  Constantin Tamvakopoulos ,  Qianping Peng ,  Randy R Miller ,  Ralph A Stearns ,  Howard Y Chen ,  Airu S Chen ,  Tung M Fong ,  Matthew J Wyvratt Jr ,  Ravi P Nargund
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]
PMID: 20598882 DOI: 10.1016/j.bmcl.2010.06.062
Abstract

We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.

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