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

H S Jae; M Winn; T W von Geldern; B K Sorensen; W J Chiou; B Nguyen; K C Marsh; T J Opgenorth

doi:10.1021/jm010237l

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.

Authors

H S Jae¹, M Winn, T W von Geldern, B K Sorensen, W J Chiou, B Nguyen, K C Marsh, T J Opgenorth

Affiliation

¹ Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. hwan-soo.jae@abbott.com

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.

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