PDE8b is a cAMP-specific isoform of the broader class of phosphosdieserases (PDEs).  As no selective PDE8 inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8b inhibition.  Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE).  These triazolo pyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 1  .  This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.                                                                                                                                     

Discovery of triazolopyrimidine-based PDE8 inhibitors:  Exceptionally ligand-efficient and lipophilic ligand-efficient compounds

243rd National Meeting (2012)

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