Optimisation of novel small molecule inhibitors of SRPK1-mediated VEGF-A splicing through modelling of permeability properties required for trans-scleral eye drop delivery

Purpose Development of non-invasive therapies for wAMD and DME has not yet been successful due to poor PK/PD properties. SRPK1 is a novel target that controls VEGF-A splicing. Delivery of potent small molecules to the retina as eye drops is an unmet need due to lack of insight into drug required properties. We used rational medicinal chemistry and permeability models to identify physicochemical properties for retinal delivery. Methods Porcine eyes were dissected, and full thickness tissue clamped into a scaffold with drug formulations facing the sclera. Tissue sections were dissected after 24 hours and compound extracted and analysed by mass spectrometry. Efficacy, toxicity and PK were evaluated in C57/Bl6 mice. PK was assessed in pigmented and albino rabbits. Results Highly potent and selective SRPK1 inhibitors with improved permeability (×10-6 cm/s) ex vivo (Compound A 1.47, Compound B 4.07) had improved PK in in vivo models. SRPK1 inhibitors did not inhibit retinal function yet inhibited laser-CNV following eye drops given to mice (EC50s<0.5 μM, n = 6–8, p < 0.05, One-way ANOVA). Conclusions Ex vivo screening enabled modelling and design of novel compounds with improved permeability and optimisation for in vivo retinal delivery.