Discovery of triazolopyrimidine-based PDE8B inhibitors: exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5721-6. doi: 10.1016/j.bmcl.2012.06.079. Epub 2012 Jul 6.

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.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / enzymology*
  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Insulin / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Ligands
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / metabolism
  • Triazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Insulin
  • Ligands
  • Pyrimidines
  • Triazoles
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDE8B protein, human