Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists.
As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.
Department of Medicinal Chemistry, Biochemistry and Physiology, Merck Research Laboratories, Rahway, NJ 07065, USA. hyun_ok@merck.com
H O
HO
Ok
L B
LB
Reigle
M R
MR
Candelore
M A
MA
Cascieri
L F
LF
Colwell
L
L
Deng
W P
WP
Feeney
M J
MJ
Forrest
G J
GJ
Hom
D E
DE
MacIntyre
C D
CD
Strader
L
L
Tota
P
P
Wang
M J
MJ
Wyvratt
M H
MH
Fisher
A E
AE
Weber
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D010080:Oxazoles / 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; D007202:Indicators and Reagents; D010080:Oxazoles; D013449:Sulfonamides