Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis)

PLoS One. 2014 Jul 22;9(7):e102449. doi: 10.1371/journal.pone.0102449. eCollection 2014.

Abstract

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.

MeSH terms

  • Administration, Intravenous
  • Allosteric Regulation
  • Animals
  • Area Under Curve
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / pharmacokinetics*
  • Cross-Over Studies
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Drug Evaluation, Preclinical
  • Female
  • Macaca fascicularis
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / pharmacokinetics*
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacokinetics*
  • Phosphodiesterase 4 Inhibitors / administration & dosage
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics*
  • Rolipram / pharmacology

Substances

  • Benzhydryl Compounds
  • D159687
  • Nootropic Agents
  • Phenylurea Compounds
  • Phosphodiesterase 4 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram

Grant support

CHDI Foundation is a privately-funded not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this manuscript, research was conducted at the contract research organization Maccine Pte Ltd. under a fee-for-service agreement. The authors listed all contributed to the conception, study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.