Abstract
Purpose:
Excessive accumulation of lipofuscin in the RPE may represent an important pathogenic factor in etiology and progression of dry AMD and Stargardt disease. RBP4 antagonists have been shown to reduce serum RBP4 and retinol, decrease concentrations of bisretinoid precursors in the retina, and inhibit bisretinoid formation in the mouse Abca4-/- model of enhanced lipofuscinogenesis. It is thought that serum retinol lowering is accomplished by RBP4 antagonists through the disruption of the retinol-dependent interaction of Retinol-Binding Protein 4 (RBP4) with transthyretin in circulation which leads to rapid renal clearance of smaller molecular weight RBP4. The purpose of this study is to provide additional elucidation of mechanism of action for RBP4 antagonists from different structural classes
Methods:
Over 400 compounds comprising different structural classes were synthesized during the course of optimization of the lead RBP4 antagonist A1120. Compounds with significantly improved in vitro potency and desired in vitro ADME characteristics were evaluated in pharmacokinetics (PK) study in rats, mice, dogs and cynomolgus monkey. Pharmacodynamics (PD) model of RBP4 lowering was generated based on compound in vitro potency, protein binding and PK characteristics. Cell culture experiments were conducted to verify the effect of RBP4 antagonists on RBP4 dynamics
Results:
Interpretation of the PK-PD data indicates that in agreement with the existing model of retinol lowering, a subset of RBP4 antagonist stimulate renal clearance and catabolism of serum RBP4. However, for a significant number of RBP4 antagonists the PK-PD model postulates the inhibitory effect of compounds on RBP4 secretion from major RBP4-producing organs (liver, adipose tissue, and kidney) to circulation. This inhibitory effect on RBP4 secretion was confirmed experimentally in vitro. Compounds from both functional classes are capable of inducing robust serum RBP4 lowering in rat, mice and monkey and can significantly reduce bisretinoid accumulation in the mouse Abca4-/- model
Conclusions:
RBP4 antagonists from both functional classes are capable of reducing lipofuscin bisretinoid accumulation in the mouse Abca4-/- model and thus may be considered as a potential treatment for dry AMD and Stargardt disease
Keywords: 412 age-related macular degeneration •
696 retinal degenerations: hereditary •
582 ipofuscin