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

As part of our investigation into the development of orally bioavailable β3 adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human β3 agonists with excellent selectivity again...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2000-10, Vol.43 (21), p.3832-3836
Main Authors: Mathvink, Robert J, Tolman, J. Samuel, Chitty, Dawn, Candelore, Mari R, Cascieri, Margaret A, Colwell, Lawrence F, Deng, Liping, Feeney, William P, Forrest, Michael J, Hom, Gary J, MacIntyre, D. Euan, Miller, Randall R, Stearns, Ralph A, Tota, Laurie, Wyvratt, Matthew J, Fisher, Michael H, Weber, Ann E
Format: Article
Language:English
Subjects:
Biological and medical sciences
Catecholaminergic system
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
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Summary:As part of our investigation into the development of orally bioavailable β3 adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human β3 agonists with excellent selectivity against other human β receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F3C-C6H4) is a potent full β3 agonist (EC50 = 3.6 nM, 94% activation) with >600-fold selectivity over the human β1 and β2 receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm000286i