Bradykinin receptor ligands: therapeutic perspectives

Key Points The kallikrein–kinin system consists of the precursor kininogens, the proteolytic kallikrein enzymes, the kinin peptides (which are produced through cleavage of kininogens by kallikreins) and two G-protein-coupled receptors (GPCRs), termed the B1 and B2 receptors, that mediate the biological effects of kinin peptides. The growing knowledge of the biological role of kinins has fuelled the development of potent and selective kinin receptor modulators as potential therapeutics. This medicinal chemistry effort, which was initiated with peptides in the 1970s, has now culminated in the production of a number of novel non-peptide antagonists, some of which are awaiting clinical trials. This article provides an overview of the kinin biology that is relevant to the roles of kinins in disease, and then considers the potential of kinin receptor modulators in various disease indications, including inflammation and pain. Kinins, which are produced by the action of kallikrein enzymes, are blood-derived local-acting peptides that have broad effects mediated by two related G-protein-coupled receptors termed the bradykinin receptors. The endogenous kallikrein–kinin system controls blood circulation and kidney function, and promotes inflammation and pain in pathological conditions, which has led to interest in developing modulators of bradykinin receptors as potential therapeutics. This review discusses recent progress in our understanding of the genetics, molecular biology and pathophysiology of kinins and their receptors, as well as developments in medicinal chemistry, which have brought us closer to therapeutic applications of kinin receptor ligands in various indications. The potential of kinin receptor antagonists as novel analgesic agents that do not result in tolerance or have a liability for abuse has attracted particular interest.