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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.

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%).

SUBMITTER: Cioffi CL

PROVIDER: S-EPMC4902181 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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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.

Cioffi Christopher L CL Racz Boglarka B Freeman Emily E EE Conlon Michael P MP Chen Ping P Stafford Douglas G DG Schwarz Daniel M C DM Zhu Lei L Kitchen Douglas B DB Barnes Keith D KD Dobri Nicoleta N Michelotti Enrique E Cywin Charles L CL Martin William H WH Pearson Paul G PG Johnson Graham G Petrukhin Konstantin K

Journal of medicinal chemistry 20150804 15

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 macul ...[more]

PMID: 26181715

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Project description:PurposeLoss of photoreceptors in atrophic age-related macular degeneration results in severe visual impairment, although some peripheral vision is retained. To restore central vision without compromising the residual peripheral field, we developed a wireless photovoltaic retinal implant (PRIMA; Pixium Vision, Paris, France) in which pixels convert images projected from video glasses using near-infrared light into electric current to stimulate the nearby inner retinal neurons.DesignWe carried out a first-in-human clinical trial to test the safety and efficacy of the prosthesis in patients with geographic atrophy (ClinicalTrials.gov identifier, NCT03333954).ParticipantsFive patients with geographic atrophy zone of at least 3 optic disc diameters, no foveal light perception, and best-corrected visual acuity of 20/400 to 20/1000 in the worse-seeing study eye.MethodsThe 2-mm wide, 30-μm thick chip, containing 378 pixels (each 100 μm in diameter), was implanted subretinally in the area of atrophy (absolute scotoma).Main outcome measuresAnatomic outcomes were assessed with fundus photography and OCT for up to 12 months of follow-up. Prosthetic vision was assessed by mapping light perception, bar orientation, letter recognition, and Landolt C acuity.ResultsIn all patients, the prosthesis was implanted successfully under the macula, although in 2 patients, it was implanted in unintended locations: within the choroid and off center by 2 mm. All 5 patients could perceive white-yellow prosthetic visual patterns with adjustable brightness in the previous scotomata. The 3 with optimal placement of the implant demonstrated prosthetic acuity of 20/460 to 20/550, and the patient with the off-center implant demonstrated 20/800 acuity. Residual natural acuity did not decrease after implantation in any patient.ConclusionsImplantation of the PRIMA did not decrease the residual natural acuity, and it restored visual sensitivity in the former scotoma in each of the 5 patients. In 3 patients with the proper placement of the chip, prosthetic visual acuity was only 10% to 30% less than the level expected from the pixel pitch (20/420). Therefore, the use of optical or electronic magnification in the glasses as well as smaller pixels in future implants may improve visual acuity even further.

Project description:Atrophic age-related macular degeneration (AMD) is the most common form of AMD accounting for 90% of patients. During atrophic AMD the waste/exchange pathway between the blood supply (choroid) and the retinal pigment epithelium (RPE) is compromised. This results in atrophy and death of the RPE cells and subsequently the photoreceptors leading to central blindness. Although the mechanisms behind AMD are unknown, the growth of fatty deposits known as drusen, have been shown to play a role in the disease. There is currently no treatment or cure for atrophic AMD. Much research focuses on developing a synthetic substrate in order to transplant healthy cells to the native Bruch's membrane (BM), however, the diseased native BM and related structures still leave potential for transplanted cells to succumb to disease. In this proof-of-concept work we electrospun poly(ethylene terephthalate) (PET) to fabricate a nanofibrous cytocompatible synthetic BM. The apical surface of the membrane was cultured with ARPE-19 cells and the underside was decorated with poly(lactic acid-co-glycolic acid) (PLGA) or poly(glycolic acid) (PGA) degradable nanoparticles by electrospraying. The membrane exhibited hydrophilicity, high tensile strength and structurally resembled the native BM. ARPE-19 cells were able to form a monolayer on the surface of the membrane and no cell invasion into the membrane was seen. The presence of both PLGA and PGA nanoparticles increased ARPE-19 cell metabolism but had no effect on cell viability. There was a decrease in pH of ARPE-19 cell culture media 7 days following culturing with the PLGA nanoparticles but this change was eliminated by 2 weeks; PGA nanoparticles had no effect on cell culture media pH. The fluorescent dye FITC was encapsulated into nanoparticles and showed sustained release from PLGA nanoparticles for 2 weeks and PGA nanoparticles for 1 day. Future work will focus on encapsulating biologically active moieties to target drusen. This could allow this novel bioactive substrate to be a potential treatment for atrophic AMD that would function two-fold: deliver the required monolayer of healthy RPE cells to the macula on a synthetic BM and remove diseased structures within the retina, restoring the waste/exchange pathway and preventing vision loss.

Project description:PurposeAppearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral-domain optical coherence tomography (SD OCT). We aimed to build SD OCT-based risk assessment models for 5-year new onset of GA and central GA on CP.DesignProspective, longitudinal study.ParticipantsAge-Related Eye Disease Study 2 Ancillary SD OCT study participants with age-related macular degeneration (AMD) with bilateral large drusen or noncentral GA and at least 1 eye without advanced disease (n = 317).MethodsFor 1 eye per participant, qualitative and quantitative SD OCT variables were derived from standardized grading and semiautomated segmentation, respectively, at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator.Main outcome measuresNew onset of CP-visible GA and central GA.ResultsOver a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SD OCT factors (P < 0.001-0.03) were: hyperreflective foci and retinal pigment epithelium (RPE) layer atrophy or absence, followed by choroid thickness in absence of subretinal drusenoid deposits, photoreceptor outer segment loss, RPE drusen complex volume, and RPE drusen complex abnormal thinning volume. For central GA, the factors (P < 0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci, and RPE layer atrophy or absence. The models yielded a calculator that computes the probabilities of CP-visible, new-onset GA and central GA after 1 to 5 years.ConclusionsFor AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model-based on age and SD OCT segmentation, drusen characteristics, and retinal pathology-for progression to CP-visible GA over up to 5 years. This calculator may simplify SD OCT grading and with future validation has a promising role as a clinical prognostic tool.

Project description:Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1β and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1β. This interaction was mediated by the binding of α4β1 and αLβ2 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, α4β1 and αLβ2 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1β, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD.

Dataset Information

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

Publications

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

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