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ID: ALA2069214
Journal: Bioorg Med Chem Lett
Title: Discovery of triazolopyrimidine-based PDE8B inhibitors: exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes.
Authors: DeNinno MP, Wright SW, Etienne JB, Olson TV, Rocke BN, Corbett JW, Kung DW, DiRico KJ, Andrews KM, Millham ML, Parker JC, Esler W, van Volkenburg M, Boyer DD, Houseknecht KL, Doran SD.
Abstract: PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B 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 triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
CiteXplore: 22858141