ABSTRACT

This chapter describes the history of the approach used to develop small-molecule antagonists to the receptor(s) for complement factor C5a. A combination of structural analysis, molecular modeling, and structure-activity studies led to the first orally active C5a receptor antagonists, compounds that have helped validate C5aR in vivo as a viable drug target. Despite the crucial roles that C5a plays in human immune defense, protracted activation or inefficient regulation of complement leading to overexpression of C5a can be detrimental to human health. In most bioassays, C5a is the most potent of all anaphylatoxins and has a broader array of proinflammatory activities than C3a and C4a. The interaction of G-protein-coupled receptors and their ligands is complex, especially in the case of polypeptide ligands, which interact via multiple regions with their receptors. The chapter focuses on discovery of small cyclic antagonists of C5a receptors, and briefly describes some of their structural and pharmacological properties related to models of inflammatory diseases.