Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R).
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.
Marsilje
Thomas H
TH
Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. tmarsiljie@gnf.org
Roses
Jonathan B
JB
Calderwood
Emily F
EF
Stroud
Stephen G
SG
Forsyth
Nancy E
NE
Blackburn
Christopher
C
Yowe
David L
DL
Miao
Wenyan
W
Drabic
Stacey V
SV
Bohane
Marie D
MD
Daniels
J Scott
JS
Li
Ping
P
Wu
Lijun
L
Patane
Michael A
MA
Claiborne
Christopher F
CF
D000818:Animals; D001665:Binding Sites; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007093:Imidazoles; D044105:Receptor, Melanocortin, Type 4; C029899:imidazole