Chemoselective amination of 5-bromo-2-chloro-3-fluoropyridine.

The chemoselective functionalization of 5-bromo-2-chloro-3-fluoropyridine (1c) is described. Catalytic amination conditions (Pd2dba3, Xantphos, base) afford exclusively the bromide substitution product (2) for both secondary amines and primary anilines. A reversal in chemoselectivity is observed under neat conditions in the absence of palladium catalysis, with substitution at the 2-chloro position preferred to generate 3. Last, selective substitution of the 3-fluoro group is achieved under SNAr conditions to afford the dihalo adduct (4)

Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor <b>1</b> led to <b>9</b> with good oral bioavailability. The key structural changes to <b>1</b> include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both <b>1</b> and <b>9</b> can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only <b>9</b> was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. <b>9</b> has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans