Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors.
|Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors.
|Year of Publication
|Castaño, Tania, Wang Huanchen, Campillo Nuria E., Ballester Sara, González-García Coral, Hernández Javier, Pérez Concepción, Cuenca Jimena, Pérez-Castillo Ana, Martínez Ana, Huertas Oscar, Gelpí Josep-Lluis, F Luque Javier, Ke Hengming, and Gil Carmen
|Animals, Anti-Inflammatory Agents, Catalytic Domain, Cells, Crystallography, Cultured, Cyclic AMP, Cyclic Nucleotide Phosphodiesterases, Drug Design, Humans, Mice, Phosphodiesterase 4 Inhibitors, Phosphodiesterase Inhibitors, Quinazolines, Structure-Activity Relationship, Type 4, Type 7, X-Ray
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 A 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.