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

Purpose Development 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 hyp...

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Bibliographic Details
Published in:Acta ophthalmologica (Oxford, England) England), 2017-09, Vol.95 (S259), p.n/a
Main Authors: Liddell, S., Toop, H., Stewart, E., Daubney, J., Bourne, J., Batson, J., Morris, J., Bates, D.
Format: Article
Language:English
Subjects:
Animal tissues
Eye
Formulations
Inhibitors
Mice
Multiple regression analysis
Permeability
Pharmacokinetics
Physicochemical properties
Regression analysis
Retina
Splicing
Vascular endothelial growth factor
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Summary:Purpose Development 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. Methods Porcine 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. Results We 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
ISSN:1755-375X
1755-3768
DOI:10.1111/j.1755-3768.2017.0F081