Fasudil

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Fasudil
Fasudil.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Pharmacokinetic data
Metabolites Hydroxyfasudil
Elimination half-life 0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
  • 5-(1,4-Diazepane-1-sulfonyl)isoquinoline
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.250.347 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H17N3O2S
Molar mass 291.37 g·mol−1
3D model (JSmol)
  • C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3
  • 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 X mark.svgN
  • Key:NGOGFTYYXHNFQH-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (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]

Contents

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

Related Research Articles

<span class="mw-page-title-main">Angiotensin</span> Group of peptide hormones in mammals

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

<span class="mw-page-title-main">Smooth muscle</span> Involuntary non-striated muscle

Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations. It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.

<span class="mw-page-title-main">Vasoconstriction</span> Narrowing of blood vessels due to the constriction of smooth muscle cells

Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in controlling hemorrhage and reducing acute blood loss. When blood vessels constrict, the flow of blood is restricted or decreased, thus retaining body heat or increasing vascular resistance. This makes the skin turn paler because less blood reaches the surface, reducing the radiation of heat. On a larger level, vasoconstriction is one mechanism by which the body regulates and maintains mean arterial pressure.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, which is the narrowing of blood vessels.

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">Endothelin</span>

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

<span class="mw-page-title-main">Myosin light-chain kinase</span> Class of kinase enzymes

Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.

<span class="mw-page-title-main">Nicorandil</span> Chemical compound

Nicorandil is a vasodilator drug used to treat angina.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

<span class="mw-page-title-main">Thromboxane A2</span> Chemical compound

Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by activating the thromboxane receptor, which results in platelet-shape change, inside-out activation of integrins, and degranulation. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation. It is also regarded as responsible for Prinzmetal's angina.

<span class="mw-page-title-main">ROCK1</span> Protein

ROCK1 is a protein serine/threonine kinase also known as rho-associated, coiled-coil-containing protein kinase 1. Other common names are ROKβ and P160ROCK. ROCK1 is a major downstream effector of the small GTPase RhoA and is a regulator of the actomyosin cytoskeleton which promotes contractile force generation. ROCK1 plays a role in cancer and in particular cell motility, metastasis, and angiogenesis.

<span class="mw-page-title-main">Myosin-light-chain phosphatase</span>

Myosin light-chain phosphatase, also called myosin phosphatase (EC 3.1.3.53; systematic name [myosin-light-chain]-phosphate phosphohydrolase), is an enzyme (specifically a serine/threonine-specific protein phosphatase) that dephosphorylates the regulatory light chain of myosin II:

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

<span class="mw-page-title-main">PPP1R12A</span> Protein-coding gene in the species Homo sapiens

Protein phosphatase 1 regulatory subunit 12A is an enzyme that in humans is encoded by the PPP1R12A gene.

<span class="mw-page-title-main">Rho-associated protein kinase</span>

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.

<span class="mw-page-title-main">Rho kinase inhibitor</span>

Rho-kinase inhibitors are a series of compounds that target rho kinase (ROCK) and inhibit the ROCK pathway. Clinical trials have found that inhibition of the ROCK pathway contributes to the cardiovascular benefits of statin therapy. Furthermore, ROCK inhibitors may have clinical applications for anti-erectile dysfunction, antihypertension, and tumor metastasis inhibition. More recently they have been studied for the treatment of glaucoma and as a therapeutic target for the treatment of cardiovascular diseases, including ischemic stroke. While statin therapy has been demonstrated to reduce the risk of major cardiovascular events, including ischemic stroke, the interplay between the ROCK pathway and statin therapy to treat and prevent strokes in older adults has not yet been proven.

Ripasudil, a derivative of fasudil, is a rho kinase inhibitor drug used for the treatment of glaucoma and ocular hypertension.

<span class="mw-page-title-main">20-Hydroxyeicosatetraenoic acid</span> Chemical compound

20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, Hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

References

  1. ↑ "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily .
  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.
  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.
  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.
  8. ↑ Jacobson S (February 18, 2021). "Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies". Businesswire.
  9. 1 2 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.
  12. 1 2 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.
  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.
  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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