ABSTRACT
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
Subject(s)
Alzheimer Disease/drug therapy , Amides/therapeutic use , Cyclin-Dependent Kinases/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Thiazoles/therapeutic use , Amides/chemical synthesis , CDC2-CDC28 Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 5 , Drug Evaluation, Preclinical , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesisABSTRACT
In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.