Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety

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• 作者：Shuwen He ; Qingmei Hong ; Zhong Lai ; David X. Yang ; Pauline C. Ting ; Jeffrey T. Kuethe ; Timothy A. Cernak ; Kevin D. Dykstra ; Donald M. Sperbeck ; Zhicai Wu ; Yang Yu ; Ginger X. Yang ; Tianying Jian ; Jian Liu ; Deodial Guiadeen ; Arto D. Krikorian ; Lisa M. Sonatore ; Judyann Wiltsie ; Jinqi Liu ; Judith N. Gorski ; Christine C. Chung ; Jack T. Gibson ; JeanMarie Lisnock ; Jianying Xiao ; Michael Wolff ; Sharon X. Tong ; Maria Madeira ; Bindhu V. Karanam ; Dong-Ming Shen ; James M. Balkovec ; Shirly Pinto ; Ravi P. Nargund ; Robert J. DeVita
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1082-1087
• 全文大小：297K
• ISSN：1948-5875

文摘

We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A_2A receptor, no ACAT1 off-target activity at 10 渭M, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.

Keywords:

DGAT1; inhibitor; benzimidazole; ACAT1; A_2A receptor; cyclohexanecarboxylic acid; lipid tolerance test; epimerization; metabolite; Ames test; skin