1 research outputs found
Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety
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<sub>2A</sub> 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, <b>5B</b> was shown to possess an
excellent selectivity profile by screening it against a panel of more
than 100 biological targets. Compound <b>5B</b> 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