Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta(3) adrenergic receptor agonist antiobesity agents

Authors
Biftu, T Feng, DD Liang, GB Kuo, H Qian, XX Naylor, EM Colandrea, VJ Candelore, MR Cascieri, MA Colwell, LF Forrest, MJ Hom, GJ MacIntyre, DE Stearns, RA Strader, CD Wyvratt, MJ Fisher, MH Weber, AE
Citation
T. Biftu et al., Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta(3) adrenergic receptor agonist antiobesity agents, BIOORG MED, 10(13), 2000, pp. 1431-1434
Citations number
4
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
10
Issue
13
Year of publication
2000
Pages
1431 - 1434
Database
ISI
SICI code
0960-894X(20000703)10:13<1431:SASOBA>2.0.ZU;2-O
Abstract
Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally b ioavailable beta(3) adrenergic receptor (AR) agonists. The 4-trifluormethox y substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta(3) AR agonist assay with 100-fold selectivity over beta(1) and beta(2) AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-d ependent glycerolemia (ED50Gly = 0.15 mg/kg): Under these conditions a hear t rate increase of 15% was observed at a dose level of 10 mg/kg. (C) 2000 P ublished by Elsevier Science Ltd. All rights reserved.