title: Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia.
abstract: A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Wanlong
authors.initials: W
authors.lastname: Jiang
authors.forename: Fabio
authors.initials: F
authors.lastname: Tucci
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Margaret
authors.initials: M
authors.lastname: Joppa
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004435:Eating / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000150:complications; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C524704:1-(2-(1-(3-dimethylaminopropionyl)amino-2-methylpropyl)-4-methylphenyl)-4-(2-methyl-3-(4-chlorophenyl)propionyl)piperazine; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D015091:beta-Alanine; D000242:Cyclic AMP