Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 17, Pages 5721-5726Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.06.079
Keywords
Phosphodiesterase 8B; PDE8B; Diabetes; Ligand efficiency; Lipophilic ligand efficiency
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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. (C) 2012 Elsevier Ltd. All rights reserved.
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