Synthesis And Sar Of Benzyl And Phenoxymethylene Oxadiazole Benzenesulfonamides As Selective Beta(3) Adrenergic Receptor Agonist Antiobesity Agents

Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta(3) adrenergic receptor (AR) agonists. The 4-trifluormethoxy 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-dependent glycerolemia (ED50Gly = 0.15 mg/kg): Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.