@article {211,
	title = {Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors},
	journal = {ChemMedChem},
	volume = {4},
	year = {2009},
	month = {2009/05//},
	pages = {866 - 876},
	abstract = {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.},
	keywords = {Animals; 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},
	author = {Castano,T. and Wang,H. and Campillo,N. E. and Ballester,S. and Gonzalez-Garcia,C. and Hernandez,J. and Perez,C. and Cuenca,J. and Perez-Castillo,A. and Martinez,A. and Huertas,O. and Gelpi,J. L. and F. J. Luque and Ke,H. and Gil,C.}
}
