Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents.
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.
Biftu
T
T
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. tesfaye_biftu@merck.com
Feng
D D
DD
Liang
G B
GB
Kuo
H
H
Qian
X
X
Naylor
E M
EM
Colandrea
V J
VJ
Candelore
M R
MR
Cascieri
M A
MA
Colwell
L F
LF
Forrest
M J
MJ
Hom
G J
GJ
MacIntyre
D E
DE
Stearns
R A
RA
Strader
C D
CD
Wyvratt
M J
MJ
Fisher
M H
MH
Weber
A E
AE
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*
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D019440:Anti-Obesity Agents; D010069:Oxadiazoles; D013449:Sulfonamides; D005990:Glycerol