Synthesis of novel melanocortin 4 receptor agonists and antagonists containing a succinamide core.
A novel series of piperazines appended to a succinamide backbone were synthesized and found to have a high affinity for the melanocortin-4 receptor (IC(50)s ranging from <0.1 to 200 nM). Both agonists and antagonists of MC4R were prepared by modifying the groups attached to the right-hand side of the succinamide. This series also exhibits a high level of selectivity (up to 7000-fold) over mouse MC1R and human MC3R.
Xi
Ning
N
Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. nxi@amgen.com
Hale
Clarence
C
Kelly
Michael G
MG
Norman
Mark H
MH
Stec
Markian
M
Xu
Shimin
S
Baumgartner
James W
JW
Fotsch
Christopher
C
D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013386:Succinates
D000577:Amides; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D013386:Succinates; C011116:succinamide