Synthesis and Stability of Hydroxyfasudil Derivatives as Prodrugs

Fasudil (HA-1077) is the first small-molecule inhibitor of Rho-kinase and has been employed for clinical treatment of cerebral vasospasm. Hydroxyfasudil, as a metabolite of fasudil, exhibited better activity than fasudil. However, it also suffered from quick metabolisation, weak lipotropy and worse penetration of the blood–brain barrier. Thus, some hydroxyfasudil derivatives such as hydroxyfasudil acetate, hydroxyfasudil phosphate and 1-methoxyfasudil as the prodrugs of hydroxyfasudil were designed and synthesised. Meanwhile, the stability of these three compounds was also investigated. Furthermore, the reason and mechanism of hydrolysis of these compounds were discussed. This work could provide a useful guide for future research.