Synthesis and Stability of Hydroxyfasudil Derivatives as Prodrugs

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.

Keywords

Hydroxyfasudil / Prodrugs / Rho-kinase / Fasudil / Stability

References

[1] Hiroaki S, Mamunur R. Development of Rho-kinase inhibitors for cardiovascular medicine[J]. Trends Pharmacol Sci, 2007, 28(6): 296-302.

[2] Yan Y, Michael DC, Li L, et al. Discovery of potent and selective urea-based ROCK inhibitors and their effects on intraocular pressure in rats[J]. J Med Chem, 2010, 1: 175-179.

[3] 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

[4] Toyotaka Y, Hiroaki S, Osamu H et al. (2005) Beneficial effect of hydroxyfasudil[J]. J Am Coll Cardiol 45:599–607

[5] Ana CV, Samantha M, Jeffrey C, et al. Radiosynthesis of N-[(11)C]-methyl-hydroxyfasudil as a new potential PET radiotracer for Rho-kinases (ROCKs)[J]. Appl Radiat Isot, 2010, 68: 325-328.

[6] Chen MZ, Liu S, Wang XR, et al. Synthesis of 1-isoquinolinol and hydroxyfasudil[J]. Chin J Org Chem, 2012, 32: 404-408. in Chinese)

[7] Shinji Y, Misato A. Selective deprotection and amidation of 2-pyridyl esters via N-methylation[J]. Tetrahedron, 2010, 66(45): 8667-8671.

[8] Michelle M, Alex MM, Anthony JK, et al. 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, 2013, 26: 1044-1047.

[9] Sean AN, Kimy Y, Nicole SF, et al. A structurally simple self-immolative reagent that provides three distinct, simultaneous responses per detection event[J]. J Org Chem, 2011, 76: 10099-10113.

[10] Anthony DS, Joseph PS, Hollis S, et al. Simple synthesis of 4-substituted 1(2H)-isoquinolinones via electrophilic trapping of lithiated mono- and dianion precursors[J]. Synth Commun, 2007, 37: 4199-4208.

[11] Li J, Chen L, Chin E, et al. Platinum(II)-catalyzed intramolecular cyclization of alkynylbenzonitriles: Synthesis of 1-alkoxyisoquinolines and isoquinolones[J]. Tetrahedron Lett, 2010, 51: 6422-6425.

[12] Liu JQ, Wulff G. 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, 2008, 130: 8044-8054.

[13] Shlomo R, David H, Dov Z. Novel oxygenation of pyridine and quinoline rings using acetyl hypofluorite[J]. J Am Chem Soc, 1987, 109: 3790-3792.