Title:Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility
Volume: 27
Issue: 14
Author(s): Vasudha Abbhi and Poonam Piplani*
Affiliation:
- University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study (UGCCAS), Panjab University, Chandigarh 160014,India
Keywords:
Glaucoma, intraocular pressure, Rho-Kinase inhibitors, trabecular meshwork, neuroprotection,
ripasudil.
Abstract: Background: Glaucoma is a progressive optic neuropathy causing visual impairment
and Retinal Ganglionic Cells (RGCs) death gradually posing a need for neuroprotective
strategies to minimize the loss of RGCs and visual field. It is recognized as a multifactorial
disease, Intraocular Pressure (IOP) being the foremost risk factor. ROCK inhibitors have been
probed for various possible indications, such as myocardial ischemia, hypertension, kidney
diseases. Their role in neuroprotection and neuronal regeneration has been suggested to be of
value in the treatment of neurological diseases, like spinal-cord injury, Alzheimer’s disease
and multiple sclerosis but recently Rho-associated Kinase inhibitors have been recognized as
potential antiglaucoma agents.
Evidence Synthesis: Rho-Kinase is a serine/threonine kinase with a kinase domain which is
constitutively active and is involved in the regulation of smooth muscle contraction and stress
fibre formation. Two isoforms of Rho-Kinase, ROCK-I (ROCK β) and ROCK-II (ROCK α)
have been identified. ROCK II plays a pathophysiological role in glaucoma and hence the inhibitors
of ROCK may be beneficial to ameliorate the vision loss. These inhibitors decrease
the intraocular pressure in the glaucomatous eye by increasing the aqueous humour outflow
through the trabecular meshwork pathway. They also act as anti-scarring agents and hence
prevent post-operative scarring after the glaucoma filtration surgery. Their major role involves
axon regeneration by increasing the optic nerve blood flow which may be useful in
treating the damaged optic neurons. These drugs act directly on the neurons in the central visual
pathway, interrupting the RGC apoptosis and therefore serve as a novel pharmacological
approach for glaucoma neuroprotection.
Conclusion: Based on the results of high-throughput screening, several Rho kinase inhibitors
have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory
activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with
inhibitory potential against the kinase and their SAR development will be intricated in the
present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment
of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials
whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this,
a detailed and updated account of ROCK II inhibitors as the next generation therapeutic
agents for glaucoma will be discussed in this review.
