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Review

Phosphodiesterase 10 inhibitors in clinical development for CNS disorders

, &
Pages 553-560 | Received 22 Jul 2016, Accepted 01 Dec 2016, Published online: 10 Dec 2016
 

ABSTRACT

Introduction: Phosphodiesterase 10 inhibitors (PDE10-I), are conceptually attractive drugs with a potential great therapeutic window as their enriched striatal localization may likely stimulate D1R and reduce D2R downstream effects. However, so far selective PDE10-I with efficacy in animal models have not shown benefit in clinical trials and unexpectedly revealed a substantial dyskinesia motor side-effect.

Areas covered: This paper reviews the underlying biological rationale of PDE10 as a target in schizophrenia, Parkinson’s and Huntington’s disease based on peer-reviewed published articles, the status of the different PDE10–I in clinical development for various CNS indications and explores possible reasons for the clinical trial failures and translational disconnect.

Expert commentary: Possible explanations include non-optimal dose and titration schedule, but more importantly the differential non-linear pharmacodynamic interactions with individual comedications, the species difference in underlying neurobiology and the differences with the rich pharmacology of successful antipsychotics. The authors also present optogenetics, DREADD (Designer Receptor Exclusively Activated by Designer Drug) technology, organoids based on iPSC (induced Pluripotent Stem Cells) and advanced computer modeling and simulation as possible new technologies to further elucidate the complex nature of the emergent properties of key neuronal circuits that drive human behavior.

Declaration of interest

H. Geerts, A. Spiros and P. Roberts are employees of In Silico Biosciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.

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