Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.

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Jain P, Flaherty PT, Yi S, Chopra I, Bleasdell G, Lipay J, Ferandin Y, Meijer L, Madura JD

Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.

Bioorg Med Chem. 2011 Jan 1;19(1):359-73. doi: 10.1016/j.bmc.2010.11.022. Epub 2010 Dec 6.

PubMed ID

21144757 [ View in PubMed

]

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 beta (Abeta) 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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Cyclin-dependent-like kinase 5	Q00535	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Seliciclib	Cyclin-dependent kinase 2	IC 50 (nM)	700	N/A	N/A	Details