Discovery and Optimization of 4-(Imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine Derivatives as Novel Phosphodiesterase 4 Inhibitors

Abstract Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to it represents the most prominent cAMP-metabolising enzyme involved in many diseases. In this study, the hit compound (PTC-209) with moderate PDE4 inhibitory activity (IC₅₀ of 4.8±0.2 μM) was discovered by screening of our internal compound library. And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC₅₀ of 0.51±0.02 μM) and remarkable metabolic stability in rat liver microsomes. The results emphasized the successful application of screening and discovery of new scaffolds that can be helpful for optimization of novel PDE4 inhibitors.