Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor.
A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).
Chen
Caroline W
CW
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Tran
Joe A
JA
Fleck
Beth A
BA
Tucci
Fabio C
FC
Jiang
Wanlong
W
Chen
Chen
C
D000577:Amides / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D017606:Chlorine Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; D017606:Chlorine Compounds; D003510:Cyclohexanes; D008024:Ligands; D010879:Piperazines; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; D000077489:Piperazine; C032519:pyrrolidine