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.
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.
Chen
Chen
C
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA. cchen@neurocrine.com
Jiang
Wanlong
W
Tucci
Fabio
F
Tran
Joe A
JA
Fleck
Beth A
BA
Hoare
Sam R
SR
Joppa
Margaret
M
Markison
Stacy
S
Wen
Jenny
J
Sai
Yang
Y
Johns
Michael
M
Madan
Ajay
A
Chen
Takung
T
Chen
Caroline W
CW
Marinkovic
Dragan
D
Arellano
Melissa
M
Saunders
John
J
Foster
Alan C
AC
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
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