Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides

• Published in: Bioorganic & medicinal chemistry letters 1999-03, Vol.9 (5), p.749-754
• Main Authors: Parmee, E R, Naylor, E M, Perkins, L, Colandrea, V J, Ok, H O, Candelore, M R, Cascieri, M A, Deng, L, Feeney, W P, Forrest, M J, Hom, G J, MacIntyre, D E, Miller, R R, Stearns, R A, Strader, C D, Tota, L, Wyvratt, M J, Fisher, M H, Weber, A E
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adrenergic beta-1 Receptor Agonists; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - pharmacokinetics; Adrenergic beta-Agonists - pharmacology; Animals; Dogs; Heart Rate - drug effects; Humans; Macaca mulatta; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta - metabolism; Receptors, Adrenergic, beta-3; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacokinetics; Urea - pharmacology
• ISSN: 0960-894X

Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.