title: Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease.
abstract: Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cioffi
authors.affiliation: §Department of Ophthalmology, Columbia University Medical Center, New York, New York 10032, United States.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Racz
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: 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.affiliation: §Department of Ophthalmology, Columbia University Medical Center, New York, New York 10032, United States.
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Dobri
authors.affiliation: #National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Enrique
authors.initials: E
authors.lastname: Michelotti
authors.affiliation: ○National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.affiliation: ⊥WHM Consulting LLC, 111 Sterling City Road, Lyme, Connecticut 06371, United States.
authors.forename: William H
authors.initials: WH
authors.lastname: Martin
authors.affiliation: ∥iCuraVision LLC, 31194 La Baya Drive, Suite 101, Westlake Village, California 91362, United States.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Pearson
authors.affiliation: ∥iCuraVision LLC, 31194 La Baya Drive, Suite 101, Westlake Village, California 91362, United States.
authors.forename: Graham
authors.initials: G
authors.lastname: Johnson
authors.affiliation: §Department of Ophthalmology, Columbia University Medical Center, New York, New York 10032, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Petrukhin
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D057092:Geographic Atrophy / Q000188:drug therapy*; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital* / Q000188:drug therapy; D061985:Madin Darby Canine Kidney Cells; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054839:Retinol-Binding Proteins, Plasma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000080362:Stargardt Disease; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D011758:Pyrroles; C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma