Fasudil

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Fasudil
Fasudil.svg
Systematic (IUPAC) name
5-(1,4-Diazepane-1-sulfonyl)isoquinoline
Clinical data
AHFS/Drugs.com International Drug Names
Pharmacokinetic data
Bioavailability well absorbed
Metabolism metabolized quickly to hydroxyfasudil
Biological half-life 0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
CAS Registry Number 103745-39-7 YesY
ATC code C04AX32
PubChem CID: 3547
IUPHAR/BPS 5181
UNII Q0CH43PGXS YesY
KEGG D07941 YesY
ChEMBL CHEMBL38380 YesY
Chemical data
Formula C14H17N3O2S
Molecular mass 291.36 g/mol
 YesY (what is this?)  (verify)

Fasudil hydrochloride (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 victims. It has been found to be effective for the treatment of pulmonary hypertension.[3] It was demonstrated in February 2009 that fasudil could also be used to enhance memory and improve the prognosis of Alzheimers patients.[4]

It is approved for use in Japan and China, but has not been approved by the United States Food and Drug Administration or by the European Medicines Agency.

Molecular mechanism[edit]

Fasudil (HA-1077) is a selective RhoA/Rho kinase(ROCK) inhibitor.[5] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of PH. 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.[5]

Angiotensin-converting enzyme (ACE) expression and angiotensin-II (Ang-II) levels[edit]

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 PH. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.[6]

Endothelial nitric oxide synthase (eNOS) expression[edit]

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.[7]

Extracellular signal-regulated kinase (ERK) activity and p27Kip1 levels[edit]

The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).[8] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.[9] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.[10] 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.[8]

See also[edit]

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

References[edit]

  1. ^ "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily. 
  2. ^ Shibuya M, Suzuki Y (September 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". No to Shinkei (in Japanese) 45 (9): 819–24. PMID 8217408. 
  3. ^ Doggrell SA (2005). "Rho-kinase inhibitors show promise in pulmonary hypertension.". Expert Opin Investig Drugs 14 (9): 1157–1159. doi:10.1517/13543784.14.9.1157. PMID 16144499. 
  4. ^ Huentelman, Matthew J.; Stephan, Dietrich A.; Talboom, Joshua; Corneveaux, Jason J.; Reiman, David M.; Gerber, Jill D.; Barnes, Carol A.; Alexander, Gene E.; Reiman, Eric M.; Bimonte-Nelson, Heather A. (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. ^ a b Nagumo, H.; Sasaki, Y.; Ono, Y.; Okamato, H.; Seto, M.; Takuwa, Y. (2000). "Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells". American Journal of Physiology 278: C57–C65. 
  6. ^ Ocaranze M.P., Prvera, P., Novoa, U., Pinto, M., Gonzalez, L., Chiong, M., Lavandero, S., and Jalil, J.E. (2011). Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension. Journal of Hypertension. 29:706-715.
  7. ^ Takemoto, M., Sun, J., Hiroko, J., Shimokawa, H., and Liao, J.K. (2002). Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase. Journal of the American Heart Association. 106:57-62.
  8. ^ a b Liu, A.; Ling, F.; Wang, D.; Wang, Q.; Lu, X.; Liu, Y. (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: 3098–3104. 
  9. ^ Delmas, C.; Manenti, S.; Boudjelal, A.; Peyssonnaux, C.; Eychene, A.; Darbon, J.R. (2001). "The p42/p44 Mitoen-activated protein kinase activation triggers p27kip1 degradation independently of CDK2/Cyclin E in NIH 3T3 cells". The Journal of Biological Chemistry 276: 34958–34965. doi:10.1074/jbc.m101714200. 
  10. ^ Rodman, D.M.; Fouty, B.W. (2003). "Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27kip1-independent pathway". Journal of the American Heart Associations 92: 501–509.