Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyzes cAMP. Currently, PDE7 is considered to be a possible target for treating inflammatory diseases.<br/>  We report herein the identification of a new thienopyrimidinone series as potent and selective PDE7 inhibitors.<br/>Thienopyridmidinone hits were discovered to be the most potent compound series from our chemical library.<br/>  Computer modeling of the hits revealed three key interactions with PDE7. We developed synthetic strategy to obtain a lead compound maintaining the interactions. In addition, to obtain a desirable lead, ligand efficiency was used as an important metric.<br/>  As a result of the study, we obtained a potent and selective lead compound with high ligand efficiency. We carried out further modifications starting from the lead. The introduction of asymmetric substituents led to more soluble compounds with good PDE7 potency. The compounds were tested in phorbol ester-induced mouse ear edema model and exhibited good potency.

Discovery of thienopyrimidinones as a new series of potent phosphodiesterase 7 inhibitors

249th National Meeting (2015)

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