Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors

Bioorg Med Chem Lett. 2015 Feb 1;25(3):649-53. doi: 10.1016/j.bmcl.2014.11.090. Epub 2014 Dec 6.

Abstract

The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.

Keywords: Aqueous solubility; Phosphodiesterase; T-cell; Thienopyrimidinone.

MeSH terms

  • Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors*
  • Cyclic Nucleotide Phosphodiesterases, Type 7 / metabolism
  • Drug Evaluation, Preclinical
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / metabolism
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Solubility
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • Protein Isoforms
  • Pyrimidines
  • Cyclic Nucleotide Phosphodiesterases, Type 7