6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Abstract Compounds ( 2 – 5 ) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC 50 value of 2.4 nM against 125 I-labeled ET-1 binding to human ET A receptors and a 170-fold selectivity for ET A over ET B receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET A selective antagonist 2p with an IC 50 value of 0.87 nM for ET A receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD 50 : 0.04 mg/kg) in the lethality model.