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.
H S Jae  1 ,  M Winn ,  T W von Geldern ,  B K Sorensen ,  W J Chiou ,  B Nguyen ,  K C Marsh ,  T J Opgenorth
Affiliations
  • 1. Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. [email protected]
PMID: 11689084 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.