title: Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach.
abstract: The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.
authors.affiliation: Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. tian.x@pg.com
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tian
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Field
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Switzer
authors.forename: Adam W
authors.initials: AW
authors.lastname: Mazur
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetino
authors.forename: John A
authors.initials: JA
authors.lastname: Wos
authors.forename: Steve M
authors.initials: SM
authors.lastname: Berberich
authors.forename: Lalith R
authors.initials: LR
authors.lastname: Jayasinghe
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Obringer
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.forename: Beth B
authors.initials: BB
authors.lastname: Pinney
authors.forename: Julie A
authors.initials: JA
authors.lastname: Farmer
authors.forename: Doreen
authors.initials: D
authors.lastname: Crossdoersen
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Sheldon
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D018716:Molecular Mimicry; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D044101:Receptors, Melanocortin / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D008024:Ligands; D011759:Pyrrolidines; D044101:Receptors, Melanocortin; D011392:Proline