Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity.
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
He
Shuwen
S
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. shuwen_he@merck.com
Ye
Zhixiong
Z
Dobbelaar
Peter H
PH
Sebhat
Iyassu K
IK
Guo
Liangqin
L
Liu
Jian
J
Jian
Tianying
T
Lai
Yingjie
Y
Franklin
Christopher L
CL
Bakshi
Raman K
RK
Dellureficio
James P
JP
Hong
Qingmei
Q
Weinberg
David H
DH
Macneil
Tanya
T
Tang
Rui
R
Strack
Alison M
AM
Tamvakopoulos
Constantin
C
Peng
Qianping
Q
Miller
Randy R
RR
Stearns
Ralph A
RA
Chen
Howard Y
HY
Chen
Airu S
AS
Fong
Tung M
TM
Wyvratt
Matthew J
MJ
Nargund
Ravi P
RP
D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000577:Amides; D019440:Anti-Obesity Agents; C470072:MC4R protein, human; C553253:MK-0489; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; D013141:Spiro Compounds