Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity |
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Authors: | Lin Linus S Lanza Thomas J Jewell James P Liu Ping Shah Shrenik K Qi Hongbo Tong Xinchun Wang Junying Xu Suoyu S Fong Tung M Shen Chun-Pyn Lao Julie Xiao Jing Chen Shearman Lauren P Stribling D Sloan Rosko Kimberly Strack Alison Marsh Donald J Feng Yue Kumar Sanjeev Samuel Koppara Yin Wenji Van der Ploeg Lex H T Goulet Mark T Hagmann William K |
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Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com |
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Abstract: | The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity. |
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