Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor.
A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.
Jiang
Wanlong
W
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Tucci
Fabio C
FC
Tran
Joe A
JA
Fleck
Beth A
BA
Wen
Jenny
J
Markison
Stacy
S
Marinkovic
Dragan
D
Chen
Caroline W
CW
Arellano
Melissa
M
Hoare
Sam R
SR
Johns
Michael
M
Foster
Alan C
AC
Saunders
John
J
Chen
Chen
C
D000478:Alkylation; D000588:Amines / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship