title: Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.
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.
authors.affiliation: Department of Medicinal Chemistry, Mylan School of Pharmacy, Duquesne University, 600 Forbes Hall, Pittsburgh, PA 15282, USA.
authors.forename: Prashi
authors.initials: P
authors.lastname: Jain
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Flaherty
authors.forename: Shuyan
authors.initials: S
authors.lastname: Yi
authors.forename: Ishveen
authors.initials: I
authors.lastname: Chopra
authors.forename: Gwenyth
authors.initials: G
authors.lastname: Bleasdell
authors.forename: Josh
authors.initials: J
authors.lastname: Lipay
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5