fasudil
{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 437193500
| IUPAC_name = 5-(1,4-Diazepane-1-sulfonyl)isoquinoline
| image = Fasudil.svg
| width = 110
| tradename =
| Drugs.com = {{drugs.com|international|fasudil}}
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| metabolites = Hydroxyfasudil
| elimination_half-life = 0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
| excretion =
| IUPHAR_ligand = 5181
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 103745-39-7
| ATC_prefix = C04
| ATC_suffix = AX32
| ATC_supplemental =
| PubChem = 3547
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB08162
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 3426
| ChEBI = 43871
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = Q0CH43PGXS
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 38380
| PDB_ligand = M77
| chemical_formula =
| C=14 | H=17 | N=3 | O=2 | S=1 | Se= | Sr= | Tc=| charge =
| smiles = C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = NGOGFTYYXHNFQH-UHFFFAOYSA-N
}}
Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator.{{Cite news |title= Drug Found That Could Reduce Risk Of Alzheimer's | url = https://www.sciencedaily.com/releases/2009/02/090202102932.htm |work= Science Daily}} Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage,{{cite journal |vauthors= Shibuya M, Suzuki Y |title= [Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877] |language= ja |journal= Nō to Shinkei - Brain and Nerve |volume= 45 |issue=9 |pages= 819–24 |date= Sep 1993 |pmid= 8217408 }} 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.{{cite journal |vauthors= Doggrell SA |title= Rho-kinase inhibitors show promise in pulmonary hypertension |journal= Expert Opinion on Investigational Drugs |volume= 14 |issue=9 |pages= 1157–9 |date= Sep 2005 |pmid= 16144499 |doi= 10.1517/13543784.14.9.1157 |s2cid= 35237787 }} 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.{{cite journal |vauthors= Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA |title= Peripheral delivery of a ROCK inhibitor improves learning and working memory |journal= Behavioral Neuroscience |volume= 123 |issue= 1 |pages= 218–23 |date= Feb 2009 |pmid= 19170447 |pmc= 2701389 |doi= 10.1037/a0014260 }}{{cite journal | vauthors = Kumar M, Bansal N | title = Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB | journal = Behavioural Brain Research | volume = 351 | pages = 4–16 | date = October 2018 | pmid = 29807069 | doi = 10.1016/j.bbr.2018.05.024 | s2cid = 44121036 }}{{cite journal | vauthors = Song X, He R, Han W, Li T, Xie L, Cheng L, Chen H, Xie M, Jiang L | display-authors = 6 | title = Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats | journal = Journal of Neuroscience Research | volume = 97 | issue = 4 | pages = 506–519 | date = April 2019 | pmid = 30421453 | doi = 10.1002/jnr.24355 | s2cid = 53289377 }}
It has been approved for use in Japan and China since 1995,{{cite journal | vauthors = Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, Xu B, Wang R | display-authors = 6 | title = Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage | journal = Neurologia Medico-Chirurgica | volume = 46 | issue = 9 | pages = 421–8 | date = September 2006 | pmid = 16998274 | doi = 10.2176/nmc.46.421 | doi-access = free }} 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.{{cite web |url=https://www.businesswire.com/news/home/20210218005184/en/ |title=Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies |last=Jacobson |first=Sven |date=February 18, 2021 |website=Businesswire}}
Molecular mechanism
Fasudil (HA-1077) is a selective RhoA/Rho kinase (ROCK) inhibitor.{{cite journal |vauthors= Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y |title= Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells |journal= American Journal of Physiology. Cell Physiology |volume= 278 |issue=1 |pages= C57–65 |date= Jan 2000 |pmid= 10644512 |doi= 10.1152/ajpcell.2000.278.1.c57|s2cid= 1158687 |doi-access= free }} 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.
= 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.{{cite journal | vauthors = Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE | title = Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension | journal = Journal of Hypertension | volume = 29 | issue = 4 | pages = 706–15 | date = Apr 2011 | pmid = 21330937 | doi = 10.1097/HJH.0b013e3283440665 | hdl = 10533/134321 | s2cid = 205630605 | hdl-access = free }}
= 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.{{cite journal | vauthors = Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK | title = Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase | journal = Circulation | volume = 106 | issue = 1 | pages = 57–62 | date = Jul 2002 | pmid = 12093770 | doi=10.1161/01.cir.0000020682.73694.ab| doi-access = free }}
= ERK activation =
The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).{{cite journal | vauthors = Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL | title = Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway | journal = Chinese Medical Journal | volume = 124 | issue = 19 | pages = 3098–104 | date = Oct 2011 | pmid = 22040563 }} ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.{{cite journal | vauthors = Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM | title = The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34958–65 | date = Sep 2001 | pmid = 11418594 | doi = 10.1074/jbc.m101714200 | doi-access = free }} p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.{{cite journal | vauthors = Fouty BW, Rodman DM | title = Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway | journal = Circulation Research | volume = 92 | issue = 5 | pages = 501–9 | date = Mar 2003 | pmid = 12600884 | doi = 10.1161/01.RES.0000061180.03813.0F | doi-access = free }} 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.
=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.{{cite journal | vauthors = 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 | title = Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. | journal = Acta Neuropathol. Commun.| volume = 4 | issue = 39 | date = April 22, 2016 | page = 39 | pmid = 27101974 | doi = 10.1186/s40478-016-0310-y| pmc = 4840958 | doi-access = free }} 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.{{cite journal | vauthors = Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE | title = Molecular basis of small-molecule binding to α-synuclein | journal = bioRxiv| date = January 24, 2021 | doi = 10.1101/2021.01.22.426549| s2cid = 231777082 | url = https://pub.dzne.de/search?p=id:%22DZNE-2022-00161%22 }}
See also
- Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension