Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1

J Med Chem. 2018 May 24;61(10):4635-4640. doi: 10.1021/acs.jmedchem.8b00374. Epub 2018 May 10.

Abstract

We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / antagonists & inhibitors*
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Myocardium / enzymology*
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Protein Conformation
  • Quinazolines / chemistry*

Substances

  • Phosphodiesterase Inhibitors
  • Quinazolines
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 1