Structure–activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2- b]pyridines

Abstract

The synthesis and structure–activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2- b]pyridine class of ET A receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates ( 3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy ( 2g and h), hydroxyalkyl ( 2i, m, and p), 3-methoxy-2-methylpropyl ( 2t and u), N-acetyl- N-methylaminomethyl ( 2v), and 2-(dimethylcarbamoyl)propyl ( 2w) derivatives that showed greater than 1000-fold selectivity for the ET A receptor over the ET B receptor with excellent binding affinity (IC 50<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl ( 2i) and 3-methoxy-2-methylpropyl ( 2u) derivatives exhibiting good oral bioavailability in rats.