Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research

Curr Drug Targets. 2019;20(1):122-143. doi: 10.2174/1389450119666180808105056.

Abstract

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.

Keywords: CNS disorders; PDE10A inhibitors; SAR study; isoquinoline; papaverine-related compounds; second messenger system..

Publication types

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

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Central Nervous System Diseases / drug therapy*
  • Central Nervous System Diseases / pathology
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / pathology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / therapeutic use
  • Phosphoric Diester Hydrolases / metabolism*
  • Signal Transduction / drug effects*
  • Treatment Outcome

Substances

  • Phosphodiesterase Inhibitors
  • Cyclic AMP
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Cyclic GMP