A catch-and-release strategy for the combinatorial synthesis of 4-acylamino-1,3-thiazoles as potential CDK5 inhibitors.
Two-dimensional libraries of 4-acylamino-1,3-thiazoles 9 were prepared via Curtius rearrangement of 1,3-thiazole-4-carbonyl azides 6, trapping of the intermediate isocyanates with oxime resin, and thermal regeneration of the isocyanates from the washed resin in the presence of nucleophiles. Several compounds proved to be selective inhibitors of CDK5/p25 versus the closely homologous CDK2/cyclin A enzyme, with the best analogue (43) possessing over 100-fold selectivity.
D020650:Combinatorial Chemistry Techniques; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013844:Thiazoles; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases