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%.

Identification of Potential Biomarkers for Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment by Vitreous iTRAQ-Based Proteomic Profiling

“…These proteins are important for maintaining cell activities and transport functions. Recently, a few studies indicated that increased RBP4 in blood may promote retinal dysfunction [34,36,37]. …”

Vitamin A: a missing link in diabetes?

“…Nevertheless, anti-T2D therapies that block RBP4 are being developed[25]. However, as RBP4 is the major carrier of serum vitamin A, a thorough understanding of how these therapeutic approaches might affect vitamin A metabolism is essential, as anti-RBP4 therapies can compromise vitamin A status in rodents and humans[33–35]. …”

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

“…3,8 We recently reported our initial efforts in this field, which are based on the hypothesis that reduction of the ocular uptake of serum all- trans retinol (retinol, vitamin A) ( 1 ) (Figure 1) via reduction in circulating levels of serum retinol binding protein 4 (RBP4) can lead to a reduced rate of bisretinoid A2E accumulation in the retina. 9 …”

“…Thus, our goal was to develop novel chemical matter with improved drug-like characteristics relative to 3 , and our efforts led to the discovery of the novel bicyclic [3.3.0]-octahydrocyclopenta[ c ]pyrrolo RBP4 antagonist 4 . 9 Analogue 4 possesses a favorable balance of suitable in vitro RBP4 binding (scintillation proximity assay (SPA)) and functional RBP4-TTR interaction antagonist (HTRF) activity with significantly improved HLM stability (100% remaining after a 30 min incubation). Furthermore, 4 possesses good pharmacokinetic (PK) and pharmacodynamic (PD) properties, leading to robust and sustained lowering (>85%) of serum RBP4 levels in both acute and chronic rodent oral dosing studies.…”

“…Furthermore, 4 possesses good pharmacokinetic (PK) and pharmacodynamic (PD) properties, leading to robust and sustained lowering (>85%) of serum RBP4 levels in both acute and chronic rodent oral dosing studies. 9 …”