title: Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. ftucci@neurocrine.com
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Nicole S
authors.initials: NS
authors.lastname: White
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Margaret
authors.initials: M
authors.lastname: Joppa
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dyck
authors.forename: Jessica
authors.initials: J
authors.lastname: Parker
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: L Melissa
authors.initials: LM
authors.lastname: Arellano
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Wanlong
authors.initials: W
authors.lastname: Jiang
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Gogas
authors.forename: Val S
authors.initials: VS
authors.lastname: Goodfellow
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: 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
chemical_list: C470072:MC4R protein, human; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4