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

Abstract

Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable β 3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC 50 of 8 nM in the β 3 AR agonist assay with 100-fold selectivity over β 1 and β 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 (ED 50Gly=0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.