title: Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors.
abstract: Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer's disease. A structure-activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Joydev K
authors.initials: JK
authors.lastname: Laha
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Lixin
authors.initials: L
authors.lastname: Qiao
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Snigdha
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D051360:Cyclin-Dependent Kinase 5