Discovery of a Potent, Orally Bioavailable β3 Adrenergic Receptor Agonist, (R)-N-[4-[2-[[2-Hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
| Autor: | Lawrence F. Colwell, William P. Feeney, Liping Deng, Michael J. Forrest, Randy R. Miller, Ralph A. Stearns, Ann E. Weber, Mari R. Candelore, Gary J Hom, D. E. Macintyre, Mathew J. Wyvratt, Dawn Chitty, Robert J. Mathvink, Tolman Js, Laurie Tota, Margaret A. Cascieri, M. H. Fisher |
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| Rok vydání: | 2000 |
| Předmět: |
Glycerol
Male Agonist Beta-3 adrenergic receptor Stereochemistry medicine.drug_class Administration Oral Biological Availability Adrenergic beta-3 Receptor Agonists CHO Cells Chemical synthesis Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Dogs Cricetinae Drug Discovery medicine Animals Humans Cloning Molecular Thiazole Beta (finance) Sulfonamides Trifluoromethyl Adrenergic beta-Agonists Macaca mulatta Rats Thiazoles chemistry Receptors Adrenergic beta-3 Molecular Medicine Receptors Adrenergic beta-2 Receptors Adrenergic beta-1 Pharmacophore |
| Zdroj: | Journal of Medicinal Chemistry. 43:3832-3836 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm000286i |
| Popis: | As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action. |
| Databáze: | OpenAIRE |
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