title: Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease.
abstract: Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.
authors.affiliation: Department of Medicinal Chemistry, Albany Molecular Research, Inc. , East Campus, C-Wing, Rensselaer, New York 12144, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cioffi
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Dobri
authors.forename: Emily E
authors.initials: EE
authors.lastname: Freeman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Conlon
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Stafford
authors.forename: Daniel M C
authors.initials: DM
authors.lastname: Schwarz
authors.forename: Kathy C
authors.initials: KC
authors.lastname: Golden
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kitchen
authors.forename: Keith D
authors.initials: KD
authors.lastname: Barnes
authors.forename: Boglarka
authors.initials: B
authors.lastname: Racz
authors.forename: Qiong
authors.initials: Q
authors.lastname: Qin
authors.forename: Enrique
authors.initials: E
authors.lastname: Michelotti
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: William H
authors.initials: WH
authors.lastname: Martin
authors.forename: Paul G
authors.initials: PG
authors.lastname: Pearson
authors.forename: Graham
authors.initials: G
authors.lastname: Johnson
authors.forename: Konstantin
authors.initials: K
authors.lastname: Petrukhin
mesh_terms: D000818:Animals; D001284:Atrophy; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D008024:Ligands; D008268:Macular Degeneration / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011228:Prealbumin / Q000037:antagonists & inhibitors; D011487:Protein Conformation; D051381:Rats; D054839:Retinol-Binding Proteins, Plasma / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000080362:Stargardt Disease; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010880:Piperidines; D011228:Prealbumin; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; C032727:piperidine