Optimisation of potent topical SRPK1 inhibitors with improved retinal pharmacokinetics through ex vivo trans‐scleral permeability modelling

Abstract

PurposeDevelopment of non‐invasive therapies for wAMD and DME has been unsuccessful to date. Delivery of potent small molecules to the retina as eye drops would be a treatment paradigm shift but remains an unmet need due to incomplete understanding of the physicochemical properties required. We hypothesised that trans‐scleral permeability modelling could identify these features and enable optimisation of inhibitors of the VEGF‐A splicing kinase SRPK1.MethodsPorcine eye tissue was clamped into a scaffold with drug formulations for 24 h. Compound levels were analysed by LCMS. For PK, Hy79b pigmented rabbits received a single eye drop for successive timepoints or tri‐daily eye drops for 6 days. Compound levels in eye tissues and plasma were analysed by LCMS. Efficacy was evaluated in vivo in C57/Bl6 mice.ResultsWe identified potent and selective SRPK1 inhibitors with improved permeability ex vivo (ranging to 8.154x10‐6 cm/s compared to 0.07x10‐6 cm/s for pazopanib). Multiple regression analysis generated predicted permeability values which correlated with ex vivo permeability and in vivo retinal PK. SRPK1 inhibitors were equally distributed across the retina at 4 h at significantly higher concentrations than pazopanib and at significantly lower concentrations in plasma. SRPK1 inhibitors potently inhibited laser‐CNV following eye drop administration in mice (EC50s<0.5 μM, n = 6‐8, P < 0.05).ConclusionsEx vivo permeability screening enabled modelling and design of novel compounds with improved permeability and optimisation for in vivo retinal delivery. Increased potency and ocular permeability of the novel SRPK1 inhibitors show potential to reach therapeutic levels in the retina following eye drop administration and improve treatment for patients with wAMD and DME.