1. Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity
- Author
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Yingjie Lai, Ralph A. Stearns, Qianping Peng, Ravi P. Nargund, Qingmei Hong, Jian Liu, Rui Tang, Matthew J. Wyvratt, Raman K. Bakshi, Randy R. Miller, Tianying Jian, Alison M. Strack, Tanya MacNeil, Liangqin Guo, Howard Y. Chen, James Dellureficio, Iyassu K. Sebhat, Peter H. Dobbelaar, Airu S. Chen, Constantin Tamvakopoulos, David H. Weinberg, Tung M. Fong, Christopher L. Franklin, Shuwen He, and Zhixiong Ye
- Subjects
Agonist ,medicine.medical_specialty ,Pyrrolidines ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Anti-Obesity Agents ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Structure–activity relationship ,Spiro Compounds ,Obesity ,Molecular Biology ,Mice, Knockout ,Chemistry ,Body Weight ,Organic Chemistry ,Amides ,Rats ,Endocrinology ,Drug development ,Anorectic ,Receptor, Melanocortin, Type 4 ,Molecular Medicine - 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.
- Published
- 2010
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