Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer’s disease

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.

Graphical abstractUsing structure-based drug design, 4-aminoimidazoles were prepared with potent inhibition of cdk5/p25 in enzyme and whole cell assays and selectivity over cdk2.Figure optionsDownload full-size imageDownload as PowerPoint slide