Discovery and Commercial Development of Cholesteryl Transfer Protein Inhibitor Evacetrapib

Novel therapies which modulate HDL metabolism and thus serve to increase HDL-c levels have been proposed as an effective strategy in reducing overall residual cardiovascular risk. As an approximation, each mg/dL increase in plasma HDL cholesterol could result in a 2 – 3% decrease in cardiovascular risk. This chapter summarizes the discovery of cholesteryl ester transfer protein (CETP) inhibitor evacetrapib (LY2484595), a molecule capable of dramatically elevating plasma levels of HDL-c. Key themes described in this summary include the discovery and structure activity relationship of the scaffold, development of enabling synthetic methods to prepare preclinical quantities for early discovery efforts, and ultimately development of a commercially viable manufacturing process.