title: Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer's disease.
abstract: Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. chris.j.helal@pfizer.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Kang
authors.forename: John C
authors.initials: JC
authors.lastname: Lucas
authors.forename: Thomas
authors.initials: T
authors.lastname: Gant
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
authors.forename: Joel B
authors.initials: JB
authors.lastname: Schachter
authors.forename: Karl E G
authors.initials: KE
authors.lastname: Richter
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Kristin
authors.initials: K
authors.lastname: Kelly
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Jay
authors.initials: J
authors.lastname: Pandit
authors.forename: Natalie
authors.initials: N
authors.lastname: Hosea
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019927:Cyclin E; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; C118136:TPPP protein, human; C098330:4-aminoimidazole; D051360:Cyclin-Dependent Kinase 5; D051357:Cyclin-Dependent Kinase 2