Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

• Identified a 5-phenylthiazole scaffold exhibiting DGAT1 inhibition.
• Compounds with this scaffold also exhibit promising pharmacokinetic parameters.
• Compound 33 may serve as a lead for developing newer anti-obesity agents.

Biphenyl carboxylic acids, exemplified by compound 5, are known potent inhibitors of diacylglycerol acyltransferase, DGAT1, an enzyme involved in the final committed step of triglyceride biosynthesis. We have synthesized and evaluated 2-phenylthiazole, 4-phenylthiazole, and 5-phenylthiazole analogs as DGAT1 inhibitors. The 5-phenylthiazole series exhibited potent DGAT1 inhibition when evaluated using an in vitro enzymatic assay and an in vivo fat tolerance test in mice. Compound 33 (IC50 = 23 nM) exhibiting promising oral pharmacokinetic parameters (AUCinf = 7058 ng*h/ml, T1/2 = 0.83 h) coupled with 87 percent reduction of plasma triglycerides in vivo may serve as a lead for developing newer anti-obesity agents.

Design, synthesis, and biological evaluation of 5-phenylthiazole containing biaryl analogs as DGAT1 inhibitors have been reported.Figure optionsDownload as PowerPoint slide