Synthesis and Pharmacological Study of Rho-Kinase Inhibitors: Pharmacomodulations on the Lead Compound Fasudil

Logé, Cédric; Siomboing, Xavier; Wallez, Valérie; Scalbert, Elizabeth; Bennejean, Caroline; Cario-Tourmaniantz, Christelle; Loirand, Gervaise; Gressier, Bernard; Pacaud, Pierre; Luyckx, M.

doi:10.1080/1475636031000093561

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…Although fasudil and Y-27632 are both ROCK inhibitors, their molecular structures are remarkably different ( Fig 1A) [28]. While Y-27632 is expensive due to its complicated synthesis process, fasudil is relatively simple to synthesize and 10-30 times cheaper than Y-27632 ( Fig 1B) [19,29].…”

Section: Comparison Of Fasudil and Y-27632mentioning

confidence: 99%

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research

Lee

Choi

et al. 2020

PLoS ONE

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Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders the maintenance and differentiation of stem cells. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative and is cheaper than Y-27632. It increased hPSC growth following thawing and passaging, like Y-27632, and did not affect pluripotency, differentiation ability, and chromosome integrity. Furthermore, fasudil promoted retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells (NCCs) during differentiation. It was also useful for single-cell passaging of hPSCs and during aggregation. These findings suggest that fasudil can replace Y-27632 for use in stem research.

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Section: Comparison Of Fasudil and Y-27632mentioning

confidence: 99%

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research

Lee

Choi

et al. 2020

PLoS ONE

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“…This small molecule also inhibits the protein kinase group AGC (PKA, PKG, and PKC), which are known to regulate the self-renewal and survival of hPSC [38,39]. While Y-27362 retains a high price due to its complicated synthesis process, fasudil is relatively simple to synthesize and about 9.8 to 29.8 times lower in price than Y-27632 ( Figure 1B) [21,22].…”

Section: Comparison Of Fasudil and Y-27632mentioning

confidence: 99%

“…There are several ROCK inhibitors available on the market, including RKI-1447, GSK429286A, H-1152, SLx-2119, TC-S 7001, and fasudil. In particular, fasudil (HA-1077, 5-[1,4diazepan-1-ylsulfonyl] isoquinoline) is synthesized only in one step, so it is much easier to synthesize than Y-27632 [22]. To date, however, fasudil has only been used in PSC culture as a control group, but it has not been clearly characterized for use with hPSCs following long-term culture [14].…”

Section: Introductionmentioning

confidence: 99%

The Rho-Associated Kinase Inhibitor Fasudil can Replace Y-27632 for Use in Human Pluripotent Stem Cell Research

So¹,

Lee²,

Park³

et al. 2019

Preprint

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Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders maintenance and differentiation in stem cell research. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative. Fasudil increased hPSC growth due to survival rather than proliferation following thawing and passaging, similar to Y-27632. It did not affect pluripotency and genetic integrity including mitochondrial genome (mtDNA). Notably, the genes related to metabolism, mTORC1, and TP53 have mainly displayed a faster recovery pattern with ROCK inhibitors than control. Furthermore, fasudil was confirmed as useful for the single dissociation of hPSCs and for aggregation. It also increased retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells during differentiation. These findings suggest that fasudil can replace Y-27632 for use in stem cell research.

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Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility

Abbhi

Piplani

2020

CMC

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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 .) and ROCK-II (ROCK .) 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.

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Synthesis and Pharmacological Study of Rho-Kinase Inhibitors: Pharmacomodulations on the Lead Compound Fasudil

Cited by 3 publications

References 19 publications

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research

The Rho-Associated Kinase Inhibitor Fasudil can Replace Y-27632 for Use in Human Pluripotent Stem Cell Research

Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility

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