Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis

J Med Chem. 2015 Oct 8;58(19):7888-94. doi: 10.1021/acs.jmedchem.5b00983. Epub 2015 Sep 25.

Abstract

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Male
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism
  • Pyrimidines / chemistry
  • Rats, Wistar
  • Schizophrenia / drug therapy
  • Structure-Activity Relationship*

Substances

  • Phosphodiesterase Inhibitors
  • Pyrimidines
  • Dizocilpine Maleate
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases

Associated data

  • PDB/5C1W
  • PDB/5C28
  • PDB/5C29
  • PDB/5C2A
  • PDB/5C2E
  • PDB/5C2H