| Literature DB >> 25349648 |
Shuwen He1, Qingmei Hong1, Zhong Lai1, David X Yang1, Pauline C Ting1, Jeffrey T Kuethe1, Timothy A Cernak1, Kevin D Dykstra1, Donald M Sperbeck1, Zhicai Wu1, Yang Yu1, Ginger X Yang1, Tianying Jian1, Jian Liu1, Deodial Guiadeen1, Arto D Krikorian1, Lisa M Sonatore1, Judyann Wiltsie1, Jinqi Liu1, Judith N Gorski1, Christine C Chung1, Jack T Gibson1, JeanMarie Lisnock1, Jianying Xiao1, Michael Wolff1, Sharon X Tong1, Maria Madeira1, Bindhu V Karanam1, Dong-Ming Shen1, James M Balkovec1, Shirly Pinto1, Ravi P Nargund1, Robert J DeVita1.
Abstract
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 A2A receptor, no ACAT1 off-target activity at 10 μM, 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.Entities:
Keywords: A2A receptor; ACAT1; Ames test; DGAT1; benzimidazole; cyclohexanecarboxylic acid; epimerization; inhibitor; lipid tolerance test; metabolite; skin
Year: 2014 PMID： 25349648 PMCID： PMC4207266 DOI： 10.1021/ml5003426
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345