Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Hiroaki S, Mamunur R (2007) Development of Rho-kinase inhibitors for cardiovascular medicine[J]. Trends Pharmacol Sci 28(6):296–302
Yan Y, Michael DC, Li L et al (2010) Discovery of potent and selective urea-based ROCK inhibitors and their effects on intraocular pressure in rats[J]. J Med Chem 1:175–179
Hiroto Y, Miyuki K, Mutsuki A et al. (2006) Molecular mechanism for the regulation of Rho-kinase by dimerization and its inhibition by fasudil[J]. Structure 14:589-600
Toyotaka Y, Hiroaki S, Osamu H et al. (2005) Beneficial effect of hydroxyfasudil[J]. J Am Coll Cardiol 45:599–607
Ana CV, Samantha M, Jeffrey C et al (2010) Radiosynthesis of N-[(11)C]-methyl-hydroxyfasudil as a new potential PET radiotracer for Rho-kinases (ROCKs)[J]. Appl Radiat Isot 68:325–328
Chen MZ, Liu S, Wang XR et al (2012) Synthesis of 1-isoquinolinol and hydroxyfasudil[J]. Chin J Org Chem 32:404–408 (in Chinese)
Shinji Y, Misato A (2010) Selective deprotection and amidation of 2-pyridyl esters via N-methylation[J]. Tetrahedron 66(45):8667–8671
Michelle M, Alex MM, Anthony JK et al (2013) The spontaneous hydrolysis of 2-pyridyl phosphate is a good model for the special mechanism for the hydrolysis of phosphate monoester monoanions[J]. J Phys Org Chem 26:1044–1047
Sean AN, Kimy Y, Nicole SF et al (2011) A structurally simple self-immolative reagent that provides three distinct, simultaneous responses per detection event[J]. J Org Chem 76:10099–10113
Anthony DS, Joseph PS, Hollis S et al (2007) Simple synthesis of 4-substituted 1(2H)-isoquinolinones via electrophilic trapping of lithiated mono- and dianion precursors[J]. Synth Commun 37:4199–4208
Li J, Chen L, Chin E et al (2010) Platinum(II)-catalyzed intramolecular cyclization of alkynylbenzonitriles: Synthesis of 1-alkoxyisoquinolines and isoquinolones[J]. Tetrahedron Lett 51:6422–6425
Liu JQ, Wulff G (2008) Functional mimicry of carboxypeptidase A by a combination of transition state stabilization and a defined orientation of catalytic moieties in molecularly imprinted polymers[J]. J Am Chem Soc 130:8044–8054
Shlomo R, David H, Dov Z (1987) Novel oxygenation of pyridine and quinoline rings using acetyl hypofluorite[J]. J Am Chem Soc 109:3790–3792
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, Y., Liu, N., Luo, H. et al. Synthesis and Stability of Hydroxyfasudil Derivatives as Prodrugs. Trans. Tianjin Univ. 23, 87–92 (2017). https://doi.org/10.1007/s12209-016-0014-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12209-016-0014-1