June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Optimisation of potent SRPK1 inhibitors through modelling of permeability properties required for trans-scleral eye drop delivery
Author Affiliations & Notes
  • Jennifer Batson
    Exonate Ltd, Cambridge, United Kingdom
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Hamish Toop
    Chemistry, University of New South Wales, Sydney, New South Wales, Australia
  • Elizabeth Stewart
    Exonate Ltd, Cambridge, United Kingdom
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • James Daubney
    Exonate Ltd, Cambridge, United Kingdom
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Jonathan Morris
    Chemistry, University of New South Wales, Sydney, New South Wales, Australia
    Exonate Ltd, Cambridge, United Kingdom
  • David O Bates
    Exonate Ltd, Cambridge, United Kingdom
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Footnotes
    Commercial Relationships   Jennifer Batson, Exonate (E), Exonate (P); Hamish Toop, Exonate (P); Elizabeth Stewart, Exonate (E); James Daubney, Exonate (E); Jonathan Morris, Exonate (F), Exonate (C), Exonate (P); David Bates, Exonate (F), Exonate (I), Exonate (C), Exonate (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1966. doi:
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    • Get Citation

      Jennifer Batson, Hamish Toop, Elizabeth Stewart, James Daubney, Jonathan Morris, David O Bates; Optimisation of potent SRPK1 inhibitors through modelling of permeability properties required for trans-scleral eye drop delivery. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1966.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Development of non-invasive therapies for wet age-related macular degeneration (wAMD) and diabetic macular oedema (DME) has been unsuccessful due to insufficient pharmacokinetic/pharmacodynamic (PK/PD) profiles to deliver efficacious doses to the retina. 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 drug properties required. We hypothesised that trans-scleral permeability modelling could identify physicochemical properties required for eye drop administration enabling optimisation of inhibitors of the VEGF-A splicing kinase SRPK1.

Methods : Freshly enucleated porcine eyes were dissected and full thickness eye tissue was clamped into a scaffold with drug formulations nearest the sclera. Tissues were dissected at 24 h. Compound levels analysed by mass spectrometry. Compounds were screened and designed from predictive modelling based on physicochemical properties. Efficacy, toxicity and PK were evaluated in vivo in C57/Bl6 mice. For PK in a larger eye, unanaesthetised Hy79b pigmented rabbits were administered a single eye drop for successive timepoints or tri-daily eye drops for 6 days then culled by anaesthetic overdose. Eyes were dissected and compound levels analysed by mass spectrometry (Mann-Whitney and Spearman tests for correlation).

Results : We identified highly potent and selective SRPK1 inhibitors with improved permeability ex vivo (Compound A 1.47x10-6 cm/s, Compound B 4.07x10-6 cm/s). Permeability did not correlate with molecular weight, SRPK1 potency or cLogP but could be affected by additional parameters such as melanin binding. Novel compounds were designed based on predicted permeability by modelling experimental data and demonstrated improved permeability ex vivo and PK in in vivo models. SRPK1 inhibitors did not inhibit retinal function yet potently inhibited laser-CNV following eye drop administration in mice (EC50s<0.5μM, n=6-8, P<0.05, One-way ANOVA).

Conclusions : Ex vivo permeability screening enabled modelling and design of novel compounds with improved permeability and optimisation for in vivo retinal delivery. Through increased potency and ocular permeability, novel SRPK1 inhibitors have potential to reach therapeutic levels in the retina following eye drop administration and improve treatment for patients with wAMD and DME.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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