Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor.
SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.
Pontillo
Joseph
J
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.
Tran
Joseph A
JA
Arellano
Melissa
M
Fleck
Beth A
BA
Huntley
Rajesh
R
Marinkovic
Dragan
D
Lanier
Marion
M
Nelson
Jodie
J
Parker
Jessica
J
Saunders
John
J
Tucci
Fabio C
FC
Jiang
Wanlong
W
Chen
Caroline W
CW
White
Nicole S
NS
Foster
Alan C
AC
Chen
Chen
C
D000818:Animals; D001596:Benzylamines / Q000737:chemistry* / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001596:Benzylamines; C470072:MC4R protein, human; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4