3-Pyridyloxypropanolamine agonists of the beta 3 adrenergic receptor with improved pharmacokinetic properties.
Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.
Weber
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AE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Ok
H O
HO
Alvaro
R F
RF
Candelore
M R
MR
Cascieri
M A
MA
Chiu
S H
SH
Deng
L
L
Forrest
M J
MJ
Hom
G J
GJ
Hutchins
J E
JE
Kao
J
J
MacIntyre
D E
DE
Mathvink
R J
RJ
McLoughlin
D
D
Miller
R R
RR
Newbold
R C
RC
Olah
T V
TV
Parmee
E R
ER
Perkins
L
L
Stearns
R A
RA
Strader
C D
CD
Szumiloski
J
J
Tang
Y S
YS
Tota
L
L
Fisher
M H
MH
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D004285:Dogs; D006801:Humans; D007700:Kinetics; D008066:Lipolysis / Q000187:drug effects; D008253:Macaca mulatta; D015394:Molecular Structure; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides