Toward the Development of a Commercial Process to Produce Muvalaplin. Part II: Preparation of the Drug Substance

Abstract

Abstract Herein, we describe the development of steps 5–7 for a large-scale process to synthesize muvalaplin, a small-molecule lipoprotein(a) inhibitor for the potential reduction of major adverse cardiovascular events in participants with established cardiovascular disease or at risk for a first cardiovascular event. Each step was optimized, leading to improvements in safety, robustness, and cost of goods that ultimately resulted in a 41% yield increase over three steps and a 60% reduction in PMI compared to the original discovery synthesis. The process was safely scaled to >100 kg, thus ensuring clinical supply and laying the foundation for a commercial route.