Chemistry:Fasudil

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Short description: Chemical compound
Fasudil
Fasudil.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Pharmacokinetic data
MetabolitesHydroxyfasudil
Elimination half-life0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
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PDB ligand
Chemical and physical data
FormulaC14H17N3O2S
Molar mass291.37 g·mol−1
3D model (JSmol)
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Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator.[1] Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage,[2] as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension.[3] It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.[4][5][6]

It has been approved for use in Japan and China since 1995,[7] but has not been approved by the United States Food and Drug Administration or by the European Medicines Agency. Woolsey Pharmaceuticals is developing BRAVYL (oral fasudil) for various neurodegenerative diseases.[8]

Molecular mechanism

Fasudil (HA-1077) is a selective RhoA/Rho kinase (ROCK) inhibitor.[9] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.[9]

ACE expression

Angiotensin-converting enzyme (ACE) is an enzyme that catalyzes the conversion of angiotensin-I (Ang-I) to angiotensin-II (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating vasoconstriction and aldosterone secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.[10]

eNOS expression

Endothelial nitric oxide synthase (eNOS) mediates the production of the vasodilator nitric oxide (NO). Pulmonary arterial cell cultures treated with fasudil showed a significant increase in eNOS mRNA levels in a dose dependent manner, and the half-life of eNOS mRNA increased 2-folds. These findings suggested that ROCK inhibition with fasudil increases eNOS expression by stabilizing eNOS mRNA, which contributed to an increase of NO level to enhance vasodilation.[11]

ERK activation

The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).[12] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.[13] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.[14] Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.[12]

Direct inhibition of α-synuclein aggregation

In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation of α-synuclein, both in vitro and in cellular models of neurodegenerative disease.[15] Aggregation of α-synuclein is a major hallmark of Parkinson's disease, and has also been observed in other neurodegenerative diseases. Physical interactions between α-synuclein and fasudil have been shown to take place with α-synuclein in the intrinsically disordered state, which places fasudil among a small number of drug-like molecules that directly interact with intrinsically disordered proteins.[16]

See also

  • Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension

References

  1. ↑ "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily. https://www.sciencedaily.com/releases/2009/02/090202102932.htm. 
  2. ↑ "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]" (in ja). Nō to Shinkei - Brain and Nerve 45 (9): 819–24. Sep 1993. PMID 8217408. 
  3. ↑ "Rho-kinase inhibitors show promise in pulmonary hypertension". Expert Opinion on Investigational Drugs 14 (9): 1157–9. Sep 2005. doi:10.1517/13543784.14.9.1157. PMID 16144499. 
  4. ↑ "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience 123 (1): 218–23. Feb 2009. doi:10.1037/a0014260. PMID 19170447. 
  5. ↑ "Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB". Behavioural Brain Research 351: 4–16. October 2018. doi:10.1016/j.bbr.2018.05.024. PMID 29807069. 
  6. ↑ "Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats". Journal of Neuroscience Research 97 (4): 506–519. April 2019. doi:10.1002/jnr.24355. PMID 30421453. 
  7. ↑ "Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage". Neurologia Medico-Chirurgica 46 (9): 421–8. September 2006. doi:10.2176/nmc.46.421. PMID 16998274. 
  8. ↑ Jacobson, Sven (February 18, 2021). "Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies". https://www.businesswire.com/news/home/20210218005184/en/. 
  9. ↑ 9.0 9.1 "Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells". American Journal of Physiology. Cell Physiology 278 (1): C57–65. Jan 2000. doi:10.1152/ajpcell.2000.278.1.c57. PMID 10644512. 
  10. ↑ "Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension". Journal of Hypertension 29 (4): 706–15. Apr 2011. doi:10.1097/HJH.0b013e3283440665. PMID 21330937. 
  11. ↑ "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation 106 (1): 57–62. Jul 2002. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770. 
  12. ↑ 12.0 12.1 "Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway". Chinese Medical Journal 124 (19): 3098–104. Oct 2011. PMID 22040563. 
  13. ↑ "The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells". The Journal of Biological Chemistry 276 (37): 34958–65. Sep 2001. doi:10.1074/jbc.m101714200. PMID 11418594. 
  14. ↑ "Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway". Circulation Research 92 (5): 501–9. Mar 2003. doi:10.1161/01.RES.0000061180.03813.0F. PMID 12600884. 
  15. ↑ "Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease.". Acta Neuropathol. Commun. 4 (39): 39. April 22, 2016. doi:10.1186/s40478-016-0310-y. PMID 27101974. 
  16. ↑ "Molecular basis of small-molecule binding to α-synuclein". bioRxiv. January 24, 2021. doi:10.1101/2021.01.22.426549. https://pub.dzne.de/search?p=id:%22DZNE-2022-00161%22. 



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