Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides.
Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.
Parmee
E R
ER
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Naylor
E M
EM
Perkins
L
L
Colandrea
V J
VJ
Ok
H O
HO
Candelore
M R
MR
Cascieri
M A
MA
Deng
L
L
Feeney
W P
WP
Forrest
M J
MJ
Hom
G J
GJ
MacIntyre
D E
DE
Miller
R R
RR
Stearns
R A
RA
Strader
C D
CD
Tota
L
L
Wyvratt
M J
MJ
Fisher
M H
MH
Weber
A E
AE
D000284:Administration, Oral; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; C112650:L 755507; C119124:L 757793; C119126:L 760087; C119125:L 764646; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D014508:Urea