Development and potential utility of dual and triple NK receptor antagonists

The mammalian tachykinin (TK) peptides and their three neurokinin (NK) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests pathophysiological relevance for TKs in various diseases including asthma, emesis and depression. The promiscuous TK-NK receptor interactions and incompletely overlapping functions mediated by each NK receptor may indicate added therapeutic benefit of using multiple NK receptor blockade. Consequently, there has been substantial pharmaceutical effort in projects to develop nonpeptide dual and triple NK receptor antagonists. This review identifies the chemical and biological approach used to develop a TK antagonist active at the three NK receptors. Clinical activity has been observed using single and/or dual NK receptor antagonists in asthma, depression/anxiety and, most notably, emesis trials but no compound with mono or multiple NK receptor antagonist activities has cleared all the development and regulatory hurdles to commercialization. Current experience indicates that potent dual and triple NK receptor-selective antagonists possessing appropriate affinity and pharmacokinetic properties can be developed. As an example, the biological and pharmacokinetic profiles of a new representative of this class of agent, SCH 206272, is detailed in the present review. Whether such agents will fulfill researchers' expectations must await further clinical trials.