Development of potent and selective small-molecule human Urotensin-II antagonists

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.

Graphical abstractThis work describes the development of potent and selective human Urotensin-II antagonists starting from lead compound 1. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and selectivity for hUT over other receptors were addressed.Figure optionsDownload full-size imageDownload as PowerPoint slide