title: Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists 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 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
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: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
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: John
authors.initials: J
authors.lastname: Saunders
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008297:Male; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; C470072:MC4R protein, human; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4