September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Development of topically administered retinal angiogenesis inhibitors with improved ocular permeability and therapeutic exposure in rabbit eyes
Author Affiliations & Notes
  • Jennifer Batson
    University of Nottingham, Nottingham, United Kingdom
    Exonate, Nottingham, United Kingdom
  • Hamish Toop
    University of New South Wales, Sydney, New South Wales, Australia
    Exonate, Nottingham, United Kingdom
  • Jonathan Rowlinson
    University of Nottingham, Nottingham, United Kingdom
    Exonate, Nottingham, United Kingdom
  • Claire Louise Allen
    University of Nottingham, Nottingham, United Kingdom
  • Gibbons Brian
    University of Nottingham, Nottingham, United Kingdom
  • Jonathan Morris
    University of New South Wales, Sydney, New South Wales, Australia
    Exonate, Nottingham, United Kingdom
  • David O Bates
    University of Nottingham, Nottingham, United Kingdom
    Exonate, Nottingham, United Kingdom
  • Footnotes
    Commercial Relationships   Jennifer Batson, Exonate (E), Exonate (P); Hamish Toop, Exonate (E), Exonate (P); Jonathan Rowlinson, Exonate (E); Claire Allen, None; Gibbons Brian, None; Jonathan Morris, Exonate (F), Exonate (I), Exonate (C), Exonate (P); David Bates, Exonate (F), Exonate (I), Exonate (C), Exonate (P), Exonate (S)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 774. doi:
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      Jennifer Batson, Hamish Toop, Jonathan Rowlinson, Claire Louise Allen, Gibbons Brian, Jonathan Morris, David O Bates; Development of topically administered retinal angiogenesis inhibitors with improved ocular permeability and therapeutic exposure in rabbit eyes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):774.

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

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Abstract

Purpose : Development of non-invasive, novel therapies for wet age-related macular degeneration (wAMD) and diabetic macular oedema (DME) is hindered by insufficient pharmacokinetics/pharmacodynamics (PK/PD) to deliver efficacy in the retina. The splicing factor kinase SRPK1 has been identified as a novel target as it controls angiogenic VEGF levels. We undertook a rational medicinal chemistry approach to specifically design novel inhibitors with physicochemical properties required for eye drop administration using experimental models of ocular permeability.

Methods : Freshly enucleated porcine eyes were dissected, and full thickness eye tissue was clamped into a scaffold containing drug formulations in the upper chamber nearest the sclera. Tissues were dissected after 24 h and compound extracted and analysed by mass spectrometry. Compounds were screened based on chemical structure, potency, selectivity, molecular weight, cLogP and structure-activity relationships for permeability to inform further chemical development. Efficacy, toxicity and PK were evaluated in vivo in C57/Bl6 mice and PK in rabbits. Following tri-daily eye drop administration for 6 days in unanaesthetised New Zealand White rabbits, animals were killed by overdose of anaesthetic. Eyes were dissected, tissues taken and compounds analysed by mass spectrometry (Mann-Whitney and Spearman tests for correlation).

Results : Potent, selective SRPK1 inhibitors had improved permeability ex vivo compared to pazopanib and regorafinib (SPHINX-A 1.47x10-6 cm/s, Pazopanib 0.07x10-6 cm/s P<0.0005). Modifications of the R1 and R2 domains, based on crystal structure analysis, led to enhanced permeability (SPHINX-B 3.46 cm/s*10-6). Permeability did not correlate with molecular weight, SRPK1 potency or cLogP but could be affected by additional parameters such as melanin binding. SPHINX-A was detected at 0.008 % of the total applied dose (84 ug) and above its target IC50 value in rabbit eyes. 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 : Through increased specificity, potency and ocular permeability, novel SRPK1 inhibitors have potential to reach therapeutic levels in posterior eye segments following eye drop administration and improve treatment for patients with wAMD and DME.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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