Fasudil Explained
Verifiedfields: | changed |
Watchedfields: | changed |
Verifiedrevid: | 437193500 |
Iupac Name: | 5-(1,4-Diazepane-1-sulfonyl)isoquinoline |
Width: | 110 |
Metabolites: | Hydroxyfasudil |
Elimination Half-Life: | 0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours. |
Iuphar Ligand: | 5181 |
Cas Number: | 103745-39-7 |
Atc Prefix: | C04 |
Atc Suffix: | AX32 |
Pubchem: | 3547 |
Drugbank: | DB08162 |
Chemspiderid: | 3426 |
Chebi: | 43871 |
Unii: | Q0CH43PGXS |
Kegg: | D07941 |
Chembl: | 38380 |
Pdb Ligand: | M77 |
C: | 14 |
H: | 17 |
N: | 3 |
O: | 2 |
S: | 1 |
Smiles: | C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3 |
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: | NGOGFTYYXHNFQH-UHFFFAOYSA-N |
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
Notes and References
- News: Drug Found That Could Reduce Risk Of Alzheimer's . Science Daily.
- Shibuya M, Suzuki Y . [Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877] . ja . Nō to Shinkei - Brain and Nerve . 45 . 9 . 819–24 . Sep 1993 . 8217408 .
- Doggrell SA . Rho-kinase inhibitors show promise in pulmonary hypertension . Expert Opinion on Investigational Drugs . 14 . 9 . 1157–9 . Sep 2005 . 16144499 . 10.1517/13543784.14.9.1157 . 35237787 .
- Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA . Peripheral delivery of a ROCK inhibitor improves learning and working memory . Behavioral Neuroscience . 123 . 1 . 218–23 . Feb 2009 . 19170447 . 2701389 . 10.1037/a0014260 .
- Kumar M, Bansal N . 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 . 29807069 . 10.1016/j.bbr.2018.05.024 . 44121036 .
- Song X, He R, Han W, Li T, Xie L, Cheng L, Chen H, Xie M, Jiang L . 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 . 30421453 . 10.1002/jnr.24355 . 53289377 .
- Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, Xu B, Wang R . 6 . 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 . 16998274 . 10.2176/nmc.46.421 . free .
- Web site: Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies . Jacobson . Sven . February 18, 2021 . Businesswire.
- Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y . 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 . 10644512 . 10.1152/ajpcell.2000.278.1.c57. 1158687 . free .
- Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE . 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 . 21330937 . 10.1097/HJH.0b013e3283440665 . 10533/134321 . 205630605 . free .
- Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK . Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase . Circulation . 106 . 1 . 57–62 . Jul 2002 . 12093770 . 10.1161/01.cir.0000020682.73694.ab. free .
- Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL . 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 . 22040563 .
- Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM . 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 . 11418594 . 10.1074/jbc.m101714200 . free .
- Fouty BW, Rodman DM . 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 . 12600884 . 10.1161/01.RES.0000061180.03813.0F . free .
- 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 . Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. . Acta Neuropathol. Commun.. 4 . 39 . April 22, 2016 . 39 . 27101974 . 10.1186/s40478-016-0310-y. 4840958 . free .
- Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE . Molecular basis of small-molecule binding to α-synuclein . bioRxiv. January 24, 2021 . 10.1101/2021.01.22.426549. 231777082 .