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

Tania Castaño, Huanchen Wang, Nuria E. Campillo, Sara Ballester, Coral González-García, Javier Hernández, Concepción Pérez, Jimena Cuenca, Ana Pérez-Castillo, Ana Martínez, Oscar Huertas, José Luis Gelpí, F. Javier Luque, Hengming Ke, Carmen Gil

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)866-876
Number of pages11
JournalChemMedChem
Volume4
Issue number5
DOIs
StatePublished - 11 May 2009
Externally publishedYes

Keywords

  • Drug design
  • Inflammation
  • PDE7
  • Thioxoquinazolines

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