Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.
Basic Information
ID: ALA1641601
Journal: Bioorg Med Chem
Title: Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.
Authors: Jain P, Flaherty PT, Yi S, Chopra I, Bleasdell G, Lipay J, Ferandin Y, Meijer L, Madura JD.
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 β (Aβ) 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.
CiteXplore: 21144757
DOI: 10.1016/j.bmc.2010.11.022
Patent ID: ┄