Design, synthesis and biological evaluations of a long-acting, hypoxia-activated prodrug of fasudil, a ROCK inhibitor, to reduce its systemic side-effects

ROCK, one of the downstream regulators of Rho, controls actomyosin cytoskeleton organization, stress fiber formation, smooth muscle contraction, and cell migration. ROCK plays an important role in the pathologies of cerebral and coronary vasospasm, hypertension, cancer, and arteriosclerosis. Pharmac...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of controlled release Vol. 334; pp. 237 - 247
Main Authors:	Al-Hilal, Taslim A., Hossain, Mohammad Anwar, Alobaida, Ahmed, Alam, Farzana, Keshavarz, Ali, Nozik-Grayck, Eva, Stenmark, Kurt R., German, Nadezhda A., Ahsan, Fakhrul
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 10-06-2021
Subjects:	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - adverse effects 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology Endothelial Cells Fasudil Humans Hypertension Hypoxia Hypoxia - drug therapy Hypoxia-activated Prodrug Prodrugs - adverse effects Prodrugs - pharmacology Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - pharmacology rho-Associated Kinases - antagonists & inhibitors Rho-kinase inhibitor Hypertension Rho-kinase inhibitor Hypoxia Prodrug Hypoxia-activated Fasudil
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	ROCK, one of the downstream regulators of Rho, controls actomyosin cytoskeleton organization, stress fiber formation, smooth muscle contraction, and cell migration. ROCK plays an important role in the pathologies of cerebral and coronary vasospasm, hypertension, cancer, and arteriosclerosis. Pharmacological-induced systemic inhibition of ROCK affects both the pathological and physiological functions of Rho-kinase, resulting in hypotension, increased heart rate, decreased lymphocyte count, and eventually cardiovascular collapse. To overcome the adverse effects of systemic ROCK inhibition, we developed a bioreductive prodrug of a ROCK inhibitor, fasudil, that functions selectively under hypoxic conditions. By masking fasudil's active site with a bioreductive 4-nitrobenzyl group, we synthesized a prodrug of fasudil that is inactive in normoxia. Reduction of the protecting group initiated by hypoxia reveals an electron-donating substituent that leads to fragmentation of the parent molecule. Under normoxia the fasudil prodrug displayed significantly reduced activity against ROCK compared to its parent compound, but under severe hypoxia the prodrug was highly effective in suppressing ROCK activity. Under hypoxia the prodrug elicited an antiproliferative effect on disease-afflicted pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. The prodrug displayed a long plasma half-life, remained inactive in the blood, and produced no drop in systemic blood pressure when compared with fasudil-treated controls. Due to its selective nature, our hypoxia-activated fasudil prodrug could be used to treat diseases where tissue-hypoxia or hypoxic cells are the pathological basis of the disease. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Taslim A. Al-Hilal: Conceptualization, Methodology, Investigation, Data Curation, Visualization, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Supervision, and Project administration. Mohammad Anwar Hossain: Methodology, Investigation, Validation, Data Curation, Formal analysis, Writing - Original Draft, Writing - Review & Editing. Ahmad Alobaida: Investigation, Validation. Farzana Alam: Methodology, Investigation. Ali Keshavarz: Formal analysis, Investigation. Eva Nozik-Grayck: Funding acquisition. Kurt R. Stenmark: Funding acquisition. Nadezhda A. German: Supervision, Writing - Original Draft, Writing - Review & Editing. Fakhrul Ahsan: Project administration, Funding acquisition, Writing - Review & Editing. Current address: Department of Clinical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA CRediT author statement T.A.A. generated the hypothesis, conceptualized, and initiated the project, designed the experiments, performed and supervised most of the studies, and co-wrote the manuscript along with M.A.H., N.A.G., and F. Alam. M.A.H. synthesized and characterized the compounds and performed the chemical degradation experiment. A.A. and A.K. helped in in-vitro and in-vivo hemodynamic studies. F.A. developed the LC-MS/MS methods for the analysis of the compounds in matrix and plasma. A.K. helped in data and statistical analysis. E.N-G and K.R.S supervised and edited the manuscript. Request for the compounds can be addressed to N.A.G. and F.A. Author contributions
ISSN:	0168-3659 1873-4995
DOI:	10.1016/j.jconrel.2021.04.030