Chapter 13: The Discovery of TRPV1 Antagonists: Turning up the Heat

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel was first cloned and characterized in late 1997 by Michael Caterina, David Julius and colleagues. In the decade that followed an explosion of research from pharmaceutical and biotech companies ensued and an elegant series of experiments, both genetic and pharmacological, positioned TRPV1 as a key target for developing novel pain therapeutics. As a result of these efforts, TRPV1 as a potential therapeutic target, as well as the progress made towards identifying selective antagonists of TRPV1, has been extensively reviewed. This chapter will not attempt to provide a comprehensive view of the TRPV1 research area, and therefore the reader is referred to a number of the excellent reviews on the subject. Rather this chapter will outline the case study of one TRPV1 antagonist program conducted at Amgen, Inc., which started from an initial high throughput screening hit and culminated in the identification of two clinical candidates, AMG 517 and AMG 628. Methods used to identify the initial hit, strategies to generate the proof-of-concept compound, and key structure-activity relationships (SAR) studies leading to AMG 517 and AMG 628 will be outlined. In addition, the preclinical and clinical profiles of AMG 517 will also be described. Finally, two subsequent approaches to eliminate or minimize the on-target hyperthermic effect observed in the clinical studies will be summarized.