Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ET(A) antagonists

J Med Chem. 2001 Nov 8;44(23):3978-84. doi: 10.1021/jm010237l.

Abstract

The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ET(A)-selective antagonist.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Biological Availability
  • CHO Cells
  • Cricetinae
  • Endothelin Receptor Antagonists*
  • Humans
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Endothelin A
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2-(3-fluoro-4-methylphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid
  • Benzofurans
  • Endothelin Receptor Antagonists
  • Pyrrolidines
  • Receptor, Endothelin A