Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
Tucci
Fabio C
FC
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. ftucci@neurocrine.com
White
Nicole S
NS
Markison
Stacy
S
Joppa
Margaret
M
Tran
Joe A
JA
Fleck
Beth A
BA
Madan
Ajay
A
Dyck
Brian P
BP
Parker
Jessica
J
Pontillo
Joseph
J
Arellano
L Melissa
LM
Marinkovic
Dragan
D
Jiang
Wanlong
W
Chen
Caroline W
CW
Gogas
Kathleen R
KR
Goodfellow
Val S
VS
Saunders
John
J
Foster
Alan C
AC
Chen
Chen
C
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002100:Cachexia / Q000188:drug therapy; D004435:Eating / Q000187:drug effects; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C470072:MC4R protein, human; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4