Selective endothelin A receptor antagonists. 3. Discovery and structure-activity relationships of a series of 4-phenoxybutanoic acid derivatives

J Med Chem. 1998 Jul 16;41(15):2732-44. doi: 10.1021/jm9707131.

Abstract

The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

MeSH terms

  • Administration, Oral
  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Cell Line
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Decerebrate State
  • Endothelin Receptor Antagonists*
  • Injections, Intravenous
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Phenylbutyrates / chemical synthesis*
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacokinetics
  • Phenylbutyrates / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Structure-Activity Relationship
  • Vasoconstriction / drug effects

Substances

  • 4-(2-cyano-5-(3-pyridylmethoxy)phenoxy)-4-(2-methylphenyl)butanoic acid
  • Endothelin Receptor Antagonists
  • Phenylbutyrates
  • Pyridines
  • Receptor, Endothelin A
  • Receptor, Endothelin B