July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Isoquinoline sulfonamides such as fasudil, H-1152, ripasudil and H-1129 produce IOP-lowering and neuroprotective effects through Rho kinase inhibition
Author Affiliations & Notes
  • Kengo Sumi
    R&D Laboratory, D. Western Therapeutics Institute, Inc., Nagoyashi, AICHI, Japan
  • Yoko Yoshida
    R&D Laboratory, D. Western Therapeutics Institute, Inc., Nagoyashi, AICHI, Japan
  • Hiroyoshi Hidaka
    R&D Laboratory, D. Western Therapeutics Institute, Inc., Nagoyashi, AICHI, Japan
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1781. doi:
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      Kengo Sumi, Yoko Yoshida, Hiroyoshi Hidaka; Isoquinoline sulfonamides such as fasudil, H-1152, ripasudil and H-1129 produce IOP-lowering and neuroprotective effects through Rho kinase inhibition. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1781.

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

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Abstract

Purpose : In the previous ARVO meeting, we reported protein kinase inhibitor, H-1129 (also known as WP-1303), a novel isoquinoline sulfonamide that binds also to Hsp90 and reduces intraocular pressure (IOP) in animal models after topical instillation. H-1129 is under Phase 2 clinical trial for the treatment of glaucoma in Japan. In order to identify characteristics of H-1129, we examined the relationship between kinase inhibition and IOP-lowering effect in rabbits by comparing between various derivatives of H-1129, such as fasudil, H-1152 and ripasudil. We also studied effects of such isoquinoline sulfonamides on human trabecular meshwork cells (HTMC) and rat retinal ganglion cells (RGC-5).

Methods : Using H-1129 and other isoquinoline sulfonamides (fasudil, H-1152, and ripasudil), ATP competitive inhibition against ROCK2, IOP-lowering action in rabbits, morphological change on HTMC, neurite outgrowth of RGC-5 and neuroprotective effect of RGC-5 under glutamate toxicity were evaluated in accordance with existing methods, and results were compared.

Results : H-1129 inhibited ROCK2 moderately at IC50 value of 230 nM as well as fasudil with IC50 value of 730 nM but H-1152 and ripasudil inhibited ROCK2 potently at IC50 values of 19 nM, 54 nM, respectively as expected. On the other hand, H-1129 reduced IOP most effectively in rabbits with maximum reduction of 4-5 mmHg and duration time 6-7 h at 0.3-1% dosing compared to other inhibitors. In cell-based assays, we discovered that H-1129 causes morphological change of HTMC at 10-30 μM, promotes neurite outgrowth of RGC-5 at 10 μg/mL and protects RGC-5 against glutamate toxicity at 0.3-1 μM as well as H-1152 or ripasudil.

Conclusions : The IOP-lowering action of H-1129 would be most likely produced by Rho kinase inhibition on TMC leading to an increase of aqueous humor outflow as well as other isoquinoline sulfonamides. Interestingly, H-1129 reduced IOP more effectively than predicted from its Rho kinase inhibition when compared to H-1152 or ripasudil. H-1129 has also the possibility of working as a retinal neuroprotective and regenerative agent to treat glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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