Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives

J Med Chem. 2001 Oct 11;44(21):3369-77. doi: 10.1021/jm000538f.

Abstract

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

MeSH terms

  • Animals
  • Biological Availability
  • Cell Line
  • Dogs
  • Drug Evaluation, Preclinical
  • Endothelin Receptor Antagonists*
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Rats
  • Receptor, Endothelin A
  • Receptors, Endothelin / metabolism
  • Solubility
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacokinetics
  • Water

Substances

  • Endothelin Receptor Antagonists
  • Pyrimidines
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • Sulfonamides
  • T 0201
  • Water