A series of benzothiazole derivatives as ROCK inhibitors have been discovered. Compounds with good biochemical and cellular potency, and sufficient kinase selectivity have been identified.
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Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase A as a Structure Surrogate.
Chembiochem
March 2018
AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA.
We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.
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Bioorg Med Chem Lett
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Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Ahmedabad 382481, Gujarat, India. Electronic address:
Rho kinase enzyme expressed in different disease conditions and involved in mediating vasoconstriction and vascular remodeling in the pathogenesis. There are two isoforms of Rho kinases, namely ROCK I and ROCK II, responsible for different physiological function due to difference in distribution, but almost similar in structure. The Rho kinase 2 belongs to AGC family and is widely distributed in brain, heart and muscles.
View Article and Find Full Text PDFNeuregulin1-β decreases interleukin-1β-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability.
J Neurochem
January 2016
Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Neuregulin-1 (NRG1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG1 gene is large and complex, transcribing more than twenty transmembrane proteins and generating a large number of isoforms in tissue and cell type-specific patterns. Within the brain, NRG1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature.
View Article and Find Full Text PDFThe inhibitor of Rho-kinase Y-27632 induces non-secretory exocytosis in PC12 cells. The influence of this compound on central synapses remains uninvestigated. We showed that Y-27632 at the concentration 100 jtM led to spontaneous [14C]glutamate release in synaptosomes, which was not accompanied by plasma membrane depolarization.
View Article and Find Full Text PDFSpinal cord injury: a systematic review of current treatment options.
Clin Orthop Relat Res
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Division of Neurosurgery, University of Toronto, and Neural Repair and Regeneration, Spinal Program, University Health Network, Toronto Western Hospital, Toronto, ON, Canada.
Background: Spinal cord injury (SCI) is a devastating event often resulting in permanent neurologic deficit. Research has revealed an understanding of mechanisms that occur after the primary injury and contribute to functional loss. By targeting these secondary mechanisms of injury, clinicians may be able to offer improved recovery after SCI.
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