Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents |
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| Authors: | Biftu T Feng D D Liang G B Kuo H Qian X Naylor E M Colandrea V J Candelore M R Cascieri M A Colwell L F Forrest M J Hom G J MacIntyre D E Stearns R A Strader C D Wyvratt M J Fisher M H Weber A E |
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| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. tesfaye_biftu@merck.com |
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| Abstract: | Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 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. |
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