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| AHFS/Drugs.com | International Drug Names |
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| Metabolites | Hydroxyfasudil |
| Eliminationhalf-life | 0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours. |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.250.347 |
| Chemical and physical data | |
| Formula | C14H17N3O2S |
| Molar mass | 291.37 g·mol−1 |
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Fasudil (INN) is a potentRho-kinase inhibitor andvasodilator.[1] Since it was discovered, it has been used for the treatment ofcerebral vasospasm, which is often due tosubarachnoid hemorrhage,[2] as well as to improve the cognitive decline seen instroke patients. It has been found to be effective for the treatment ofpulmonary hypertension.[3] It has been demonstrated that fasudil could improvememory in normal mice, identifying the drug as a possibletreatment forage-related orneurodegenerative memory loss.[4][5][6]
It has been approved for use in Japan and China since 1995,[7] but has not been approved by theUnited States Food and Drug Administration or by theEuropean Medicines Agency. Woolsey Pharmaceuticals is developing BRAVYL (oral fasudil) for various neurodegenerative diseases.[8]
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]
Angiotensin-converting enzyme (ACE) is an enzyme that catalyzes the conversion ofangiotensin-I (Ang-I) toangiotensin-II (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiatingvasoconstriction andaldosterone 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]
Endothelial nitric oxide synthase (eNOS) mediates the production of the vasodilatornitric 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]
The proliferative effects of ROCK on vascular endothelial cells is due to the activation ofextracellular signal-regulated kinase (ERK).[12] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate ofp27Kip1.[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]
In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation ofα-synuclein, bothin vitro and in cellular models of neurodegenerative disease.[15] Aggregation of α-synuclein is a major hallmark ofParkinson'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 theintrinsically disordered state, which places fasudil among a small number of drug-like molecules that directly interact with intrinsically disordered proteins.[16]