Identification and Development of AMG 986: A Potent and Efficacious APJ Agonist for the Treatment of Heart Failure

This chapter describes the discovery and development of AMG 986. The rationale for targeting an agonist of the apelin receptor is discussed as well as the structure-activity relationship and Medicinal Chemistry efforts pursued that led to AMG 986. To alleviate a severe synthetic bottleneck, early collaboration between Medicinal Chemistry and Process Chemistry on a novel route to a key chiral sulfonamide fragment was initiated prior to final clinical candidate selection. The discovery, optimization, and scale-up of the improved stereospecific route along with the results from multi-kilogram scale-up of the improved synthetic route to AMG 986 will be discussed.