Gerald R. Girard

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.

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 kappa-opioid receptor was also explored.

D and L-N-[(1-benzyl-1H-imidazol-5-yl)-alkyl]-amino acids as angiotensin II AT-1 antagonists

Abstract A series of D and L-N-[(1-benzyl-1H-imidazol-5-yl)-alkyl]-aromatic amino acids ( 2 to 9 ) and several achiral analogs ( 1,10,11 ) were found to be potent AII antagonists (nM range). Among chiral pairs the D isomer had the highest affinity for the binding site. A D-phenylalanine analog, 3 , was the most potent (IC 50 3.8 nM) and had activity in vivo similar to SK&F 108566 when given i.v. but was only marginally active when given i.d.

A potent long-acting imidazole-5-acrylic acid angiotensin II AT-1 receptor antagonist

Abstract SB 203220 (9), the naphthyl analog of SK&F 108566(1), is a potent long-acting AT-1 antagonist. In comparison to 1, which is a competitive antagonist, 9 is a partially unsurmountable antagonist with a slower receptor off-rate, a greater resistance to tissue washout, and is more highly protein bound.