Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors

In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.

Graphical abstractThe discovery and SAR studies of a phenyloxazole based diacylglycerol acyltransferase-1 inhibitor are reported. The optimized compound 25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.Figure optionsDownload full-size imageDownload as PowerPoint slide