title: Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. tesfaye_biftu@merck.com
authors.forename: T
authors.initials: T
authors.lastname: Biftu
authors.forename: D D
authors.initials: DD
authors.lastname: Feng
authors.forename: G B
authors.initials: GB
authors.lastname: Liang
authors.forename: H
authors.initials: H
authors.lastname: Kuo
authors.forename: X
authors.initials: X
authors.lastname: Qian
authors.forename: E M
authors.initials: EM
authors.lastname: Naylor
authors.forename: V J
authors.initials: VJ
authors.lastname: Colandrea
authors.forename: M R
authors.initials: MR
authors.lastname: Candelore
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: L F
authors.initials: LF
authors.lastname: Colwell
authors.forename: M J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: G J
authors.initials: GJ
authors.lastname: Hom
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
authors.forename: C D
authors.initials: CD
authors.lastname: Strader
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D015195:Drug Design; D005990:Glycerol / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D019440:Anti-Obesity Agents; D010069:Oxadiazoles; D013449:Sulfonamides; D005990:Glycerol