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

J Med Chem 2001 Nov;44(23):3978-84

Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.

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.

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http://dx.doi.org/10.1021/jm010237lDOI Listing
November 2001
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