Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25 |
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Authors: | Jain Prashi Flaherty Patrick T Yi Shuyan Chopra Ishveen Bleasdell Gwenyth Lipay Josh Ferandin Yoan Meijer Laurent Madura Jeffry D |
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Institution: | a Department of Medicinal Chemistry, Mylan School of Pharmacy, Duquesne University, 600 Forbes Hall, Pittsburgh, PA 15282, USA b Bayer School of Natural and Environmental Sciences, Department of Chemistry, Duquesne University, 600 Forbes Hall, Pittsburgh, PA 15282, USA c CNRS, Station Biologique, 29680 Roscoff, France |
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Abstract: | Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid ?? (A??) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associated protein in neurons and stabilizes microtubules (MTs). Cyclin dependent kinase 5 (CDK5), when activated by the regulatory binding protein p25, phosphorylates tau at a number of proline-directed serine/threonine residues, resulting in formation of phosphorylated tau as paired helical filaments (PHFs) then in subsequent deposition of PHFs as NFTs. Beginning with the structure of Roscovitine, a moderately selective CDK5 inhibitor, we sought to conduct structural modifications to increase inhibitory potency of CDK5 and increase selectivity over a similar enzyme, cyclin dependent kinase 2 (CDK2). The design, synthesis, and testing of a series of 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles is presented. |
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Keywords: | CDK5 Cyclin dependent kinase Benzimidazole 1-Isopropyl benzimidazole |
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