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Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors

Posted June 8th, 2010 by pschmidtke
TitleSynthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors
Publication TypeJournal Article
Year of Publication2009
AuthorsCastano, T, Wang H, Campillo NE, Ballester S, Gonzalez-Garcia C, Hernandez J, Perez C, Cuenca J, Perez-Castillo A, Martinez A, Huertas O, Gelpi JL, Luque FJ, Ke H, Gil C
JournalChemMedChem
Volume4
Issue5
Pagination866 - 876
Date Published2009/05//
KeywordsAnimals; Anti-Inflammatory Agents/chemical synthesis/chemistry/pharmacology; Catalytic Domain; Cells, Cultured; Crystallography, Type 4/antagonists & inhibitors/metabolism; Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors/metabolism; Drug Design; Humans; Mice; Phosphodiesterase Inhibitors/chemical synthesis/chemistry/pharmacology; Quinazolines/chemical synthesis/chemistry/pharmacology; Structure-Activity Relationship, X-Ray; Cyclic AMP/metabolism; Cyclic Nucleotide Phosphodiesterases
AbstractPDE7 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.