Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor.
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.
Jiang
Wanlong
W
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Tran
Joe A
JA
Tucci
Fabio C
FC
Fleck
Beth A
BA
Hoare
Sam R
SR
Markison
Stacy
S
Wen
Jenny
J
Chen
Caroline W
CW
Marinkovic
Dragan
D
Arellano
Melissa
M
Foster
Alan C
AC
Chen
Chen
C
D000818:Animals; D001682:Biological Availability; D006801:Humans; D007275:Injections, Intravenous; D011485:Protein Binding / Q000502:physiology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism
C470072:MC4R protein, human; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; C032519:pyrrolidine