Bicyclic [3.3.0]-Octahydrocyclopenta[<i>c</i>]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Cioffi, Christopher; Rácz, Bóglárka; Freeman, Emily; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M. C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique L.; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin

doi:10.1021/acs.jmedchem.5b00423

Cited by 28 publications

(61 citation statements)

References 44 publications

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“…One of the identified analogs, BPN-14136 ( Fig. 1), has excellent drug-like characteristics and demonstrates exceptional in vitro efficacy and selectivity (37). Here, we describe the in vivo efficacy of BPN-14136 in inducing partial reduction of serum RBP4 and visual cycle retinoids such as retinaldehydes, robust inhibition of bisretinoid synthesis, and normalization of complement system dysregulation.…”

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confidence: 87%

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle

Rácz

Váradi

Kong

et al. 2018

Journal of Biological Chemistry

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A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.

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confidence: 87%

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle

Rácz

Váradi

Kong

et al. 2018

Journal of Biological Chemistry

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“…Unlike fenretinide, A1120 does not activate retinoic acid receptors. Structural modifications made to the core of the model have improved its metabolic stability (53).…”

Section: Therapeutic Approaches That Target Bisretinoid: Clinical Andmentioning

confidence: 99%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

Proc. Natl. Acad. Sci. U.S.A.

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Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

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“…To enhance the RBP4-binding affinity and metabolic stability, chemical modifications of A1120 have drawn much attention. [130][131][132] Using A1120 as a template, bicyclic-octahydrocyclopenta[c]-pyrrolo analogues have been synthesized that display more favorable RBP-binding potency and inhibition effects on lipofuscin formation. 131,132 a-Phenyl-N-tert-butylnitrone (PBN), a free radical spin trap, may have the capacity to inhibit RPE65 activity, and to protect photoreceptor cells by means of free radical scavenging and c-fos suppression.…”

Section: Chemically Synthesized Regulators Of the Retinoid Metabolismmentioning

confidence: 99%

“…[130][131][132] Using A1120 as a template, bicyclic-octahydrocyclopenta[c]-pyrrolo analogues have been synthesized that display more favorable RBP-binding potency and inhibition effects on lipofuscin formation. 131,132 a-Phenyl-N-tert-butylnitrone (PBN), a free radical spin trap, may have the capacity to inhibit RPE65 activity, and to protect photoreceptor cells by means of free radical scavenging and c-fos suppression. 15 Although a delayed recovery of rod response function is observed in laboratory animals treated with PBN, the cone visual cycle is not significantly affected, such that the extent of night blindness after PBN treatment is supposed to be slight.…”

Section: Chemically Synthesized Regulators Of the Retinoid Metabolismmentioning

confidence: 99%

Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids

Liu

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. Deficiencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt's disease, and Leber's congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina.

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Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Cited by 28 publications

References 44 publications

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids

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