Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the κ-opioid receptor was also explored.

Graphical abstractRedesign of the potent human urotensin-II antagonist 1 with the 2-pyrrolidinylmethyl-3-phenyl-piperidine core to a new chemical series with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in 17 resulted in compounds with improved PK profiles.Figure optionsDownload full-size imageDownload as PowerPoint slide