Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor.
SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K(i) values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation ( approximately 15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC(50)=36 nM).
Pontillo
Joseph
J
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Tran
Joseph A
JA
Fleck
Beth A
BA
Marinkovic
Dragan
D
Arellano
Melissa
M
Tucci
Fabio C
FC
Lanier
Marion
M
Nelson
Jodie
J
Parker
Jessica
J
Saunders
John
J
Murphy
Brian
B
Foster
Alan C
AC
Chen
Chen
C
D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001596:Benzylamines; C470072:MC4R protein, human; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4