title: Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor.
abstract: 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.
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: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: 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
chemical_list: C470072:MC4R protein, human; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; C032519:pyrrolidine