Detalle de: Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors

PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs particularly useful for treatment of a wide variety of immune and inflammatory disorders. Structural optimization of thioxoquinazoline derivatives led to new compounds with very interesting profiles as PDE7 or PDE7/PDE4 dual inhibitors, which may be further developed as new drugs for inflammatory and neurological diseases. magnified image PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs especially useful in the treatment of a wide variety of immune and inflammatory disorders. Starting from our lead family of thioxoquinazolines, we designed, synthesized, and characterized a novel series of thioxoquinazoline derivatives. Many of these compounds showed inhibitory potencies at sub‐micromolar levels against the catalytic domain of PDE7A1 and at the micromolar level against PDE4D2. Cell‐based studies showed that these compounds not only increased intracellular cAMP levels, but also had interesting anti‐inflammatory properties within a therapeutic window. The in silico data predict that these compounds are capable of the crossing the blood–brain barrier. The X‐ray crystal structure of the PDE7A1 catalytic domain in complex with compound 15 at a resolution of 2.4 Å demonstrated that hydrophobic interactions at the active site pocket are a key feature. This structure, together with molecular modeling, provides insight into the selectivity of the PDE inhibitors and a template for the discovery of new PDE7 or PDE7/PDE4 dual inhibitors.