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Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity
- Source :
- Bioorganic & Medicinal Chemistry. 7:991-1002
- Publication Year :
- 1999
- Publisher :
- Elsevier BV, 1999.
-
Abstract
- Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET A and ET B receptors. The ET A receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET B receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET A -selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET A -selective, ET B -selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET A selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.
- Subjects :
- Endothelin Receptor Antagonists
medicine.hormone
Pyrrolidines
Endothelin receptor type A
Clinical Biochemistry
Drug Evaluation, Preclinical
Pharmaceutical Science
Vasodilation
Biochemistry
Pyrrolidine
Nitric oxide
Endothelins
Structure-Activity Relationship
chemistry.chemical_compound
Drug Discovery
medicine
Animals
Receptor
Molecular Biology
Cell growth
Organic Chemistry
Receptor, Endothelin A
Rats
chemistry
Atrasentan
Molecular Medicine
Endothelin receptor
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....774eb920ffc93a25410b5a8ff75a0d43