title: Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
authors.forename: Wanlong
authors.initials: W
authors.lastname: Jiang
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: 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