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


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 ?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.

SUBMITTER: He S 

PROVIDER: S-EPMC4207266 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

He Shuwen S   Hong Qingmei Q   Lai Zhong Z   Yang David X DX   Ting Pauline C PC   Kuethe Jeffrey T JT   Cernak Timothy A TA   Dykstra Kevin D KD   Sperbeck Donald M DM   Wu Zhicai Z   Yu Yang Y   Yang Ginger X GX   Jian Tianying T   Liu Jian J   Guiadeen Deodial D   Krikorian Arto D AD   Sonatore Lisa M LM   Wiltsie Judyann J   Liu Jinqi J   Gorski Judith N JN   Chung Christine C CC   Gibson Jack T JT   Lisnock JeanMarie J   Xiao Jianying J   Wolff Michael M   Tong Sharon X SX   Madeira Maria M   Karanam Bindhu V BV   Shen Dong-Ming DM   Balkovec James M JM   Pinto Shirly S   Nargund Ravi P RP   DeVita Robert J RJ  

ACS medicinal chemistry letters 20140908 10


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 screeni  ...[more]

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