Fasudil

Fasudil
Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	C04AX32 (WHO) ;
Pharmacokinetic data
Metabolites	Hydroxyfasudil
Elimination half-life	0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
	IUPAC name 5-(1,4-Diazepane-1-sulfonyl)isoquinoline;
CAS Number	103745-39-7 ;
PubChem CID	3547;
IUPHAR/BPS	5181;
DrugBank	DB08162 ;
ChemSpider	3426 ;
UNII	Q0CH43PGXS;
KEGG	D07941 ;
ChEBI	CHEBI:43871;
ChEMBL	ChEMBL38380 ;
PDB ligand	M77 (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID4048569 ;
ECHA InfoCard	100.250.347
Chemical and physical data
Formula	C14H17N3O2S
Molar mass	291.37 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3;
	InChI InChI=1S/C14H17N3O2S/c18-20(19,17-9-2-6-15-8-10-17)14-4-1-3-12-11-16-7-5-13(12)14/h1,3-5,7,11,15H,2,6,8-10H2 ; Key:NGOGFTYYXHNFQH-UHFFFAOYSA-N ;
	(what is this?) (verify)

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]

References

^ "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily.
^ Shibuya M, Suzuki Y (Sep 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". Nō to Shinkei - Brain and Nerve (in Japanese). 45 (9): 819–24. PMID 8217408.
^ Doggrell SA (Sep 2005). "Rho-kinase inhibitors show promise in pulmonary hypertension". Expert Opinion on Investigational Drugs. 14 (9): 1157–9. doi:10.1517/13543784.14.9.1157. PMID 16144499. S2CID 35237787.
^ Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA (Feb 2009). "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience. 123 (1): 218–23. doi:10.1037/a0014260. PMC 2701389. PMID 19170447.
^ Kumar M, Bansal N (October 2018). "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. doi:10.1016/j.bbr.2018.05.024. PMID 29807069. S2CID 44121036.
^ Song X, He R, Han W, Li T, Xie L, Cheng L, et al. (April 2019). "Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats". Journal of Neuroscience Research. 97 (4): 506–519. doi:10.1002/jnr.24355. PMID 30421453. S2CID 53289377.
^ Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, et al. (September 2006). "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. doi:10.2176/nmc.46.421. PMID 16998274.
^ Jacobson S (February 18, 2021). "Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies". Businesswire.
^ ^a ^b Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y (Jan 2000). "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. doi:10.1152/ajpcell.2000.278.1.c57. PMID 10644512. S2CID 1158687.
^ Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE (Apr 2011). "Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension". Journal of Hypertension. 29 (4): 706–15. doi:10.1097/HJH.0b013e3283440665. hdl:10533/134321. PMID 21330937. S2CID 205630605.
^ Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (Jul 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation. 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.
^ ^a ^b Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL (Oct 2011). "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. PMID 22040563.
^ Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM (Sep 2001). "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. doi:10.1074/jbc.m101714200. PMID 11418594.
^ Fouty BW, Rodman DM (Mar 2003). "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. doi:10.1161/01.RES.0000061180.03813.0F. PMID 12600884.
^ Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tönges L, Bähr M, Outeiro TF, Zweckstetter M, Lingor P (April 22, 2016). "Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease". Acta Neuropathol. Commun. 4 (39): 39. doi:10.1186/s40478-016-0310-y. PMC 4840958. PMID 27101974.
^ Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE (January 24, 2021). "Molecular basis of small-molecule binding to α-synuclein". bioRxiv. doi:10.1101/2021.01.22.426549. S2CID 231777082.

[1] "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily.

[pmid8217408-2] Shibuya M, Suzuki Y (Sep 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". Nō to Shinkei - Brain and Nerve (in Japanese). 45 (9): 819–24. PMID 8217408.

[Doggrell2005-3] Doggrell SA (Sep 2005). "Rho-kinase inhibitors show promise in pulmonary hypertension". Expert Opinion on Investigational Drugs. 14 (9): 1157–9. doi:10.1517/13543784.14.9.1157. PMID 16144499. S2CID 35237787.

[Huentelman2009-4] Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA (Feb 2009). "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience. 123 (1): 218–23. doi:10.1037/a0014260. PMC 2701389. PMID 19170447.

[5] Kumar M, Bansal N (October 2018). "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. doi:10.1016/j.bbr.2018.05.024. PMID 29807069. S2CID 44121036.

[6] Song X, He R, Han W, Li T, Xie L, Cheng L, et al. (April 2019). "Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats". Journal of Neuroscience Research. 97 (4): 506–519. doi:10.1002/jnr.24355. PMID 30421453. S2CID 53289377.

[7] Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, et al. (September 2006). "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. doi:10.2176/nmc.46.421. PMID 16998274.

[jacobson-8] Jacobson S (February 18, 2021). "Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies". Businesswire.

[Nagumo_2000-9] Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y (Jan 2000). "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. doi:10.1152/ajpcell.2000.278.1.c57. PMID 10644512. S2CID 1158687.

[10] Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE (Apr 2011). "Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension". Journal of Hypertension. 29 (4): 706–15. doi:10.1097/HJH.0b013e3283440665. hdl:10533/134321. PMID 21330937. S2CID 205630605.

[11] Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (Jul 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation. 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.

[Liu_2011-12] Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL (Oct 2011). "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. PMID 22040563.

[13] Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM (Sep 2001). "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. doi:10.1074/jbc.m101714200. PMID 11418594.

[14] Fouty BW, Rodman DM (Mar 2003). "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. doi:10.1161/01.RES.0000061180.03813.0F. PMID 12600884.

[Tatenhorst_2016-15] Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tönges L, Bähr M, Outeiro TF, Zweckstetter M, Lingor P (April 22, 2016). "Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease". Acta Neuropathol. Commun. 4 (39): 39. doi:10.1186/s40478-016-0310-y. PMC 4840958. PMID 27101974.

[Zhu_2021-16] Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE (January 24, 2021). "Molecular basis of small-molecule binding to α-synuclein". bioRxiv. doi:10.1101/2021.01.22.426549. S2CID 231777082.

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[3]

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[5]

[6]

[7]

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[9]

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[12]

[13]

[14]

[15]

[16]

Fasudil

Molecular mechanism

ACE expression

eNOS expression

ERK activation

Direct inhibition of α-synuclein aggregation

See also

References

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