Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity.
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Liu
Jian
J
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. jian_liu@merck.com
He
Shuwen
S
Jian
Tianying
T
Dobbelaar
Peter H
PH
Sebhat
Iyassu K
IK
Lin
Linus S
LS
Goodman
Allan
A
Guo
Cheng
C
Guzzo
Peter R
PR
Hadden
Mark
M
Henderson
Alan J
AJ
Pattamana
Kevin
K
Ruenz
Megan
M
Sargent
Bruce J
BJ
Swenson
Brian
B
Yet
Larry
L
Tamvakopoulos
Constantin
C
Peng
Qianping
Q
Pan
Jie
J
Kan
Yanqing
Y
Palyha
Oksana
O
Kelly
Theresa M
TM
Guan
Xiao-Ming
XM
Howard
Andrew D
AD
Marsh
Donald J
DJ
Metzger
Joseph M
JM
Reitman
Marc L
ML
Wyvratt
Matthew J
MJ
Nargund
Ravi P
RP
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D018004:Receptors, Bombesin / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
C550526:2-(2-(4-(pyridin-2-yl)phenyl)ethyl)-5-(2,2-dimethylbutyl)-1H-imidazole; D007093:Imidazoles; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3