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THPP-1

Inhibitor of PDE10A

Structure

Information

  • PDE10A
  • Inhibitor
  • 10 nM
  • Reviewer recommended concentration: 50-200 nM

In Vitro Validations

Uniprot ID: Q9Y233
Target Class: Epigenetic
Target SubClass: Phosphodiesterase
Potency: Ki
Potency Value: 0.99 nM
Potency Assay: Phosphodiesterase (PDE) activity was determined using an IMAP® FP kit
PDB ID for probe-target interaction (3D structure): 3UI7
Target aliases:
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphod ...

DOI Reference: 10.1016/j.bmcl.2012.07.072

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

PDE selectivity: closest hit is PDE6A (44 fold)

Probe Selectivity in Cell:

Closest off-targets (Panlabs): Adenosine transporter (guinea pig): IC50 = 1.61 µM @ 10 µM

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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

THPP-1 is a high quality, selective and potent probe to study PDE10A inhibition in vitro or in vivo. It demonstrated in vivo target engagement and efficacy at a dose (10 mg/kg) that is well tolerated in rats. The cell line used to determine cellular IC50 was not reported and the IC50 value of 49 nM may vary with cell lines. THPP-1 showed good PK profile in rats, dogs and rhesus monkeys and efficacy in rats and rhesus schizophrenia models. Of the three species, in vitro potency and in vivo target engagement (by measurement of cGMP striatum level) were only determined in rats so it is unclear what dose is necessary to study THPP-1 pharmacology in other species. Of note, expression of PDE10A is restricted to the brain and free brain exposure was not determined for the reported in vivo studies. CSF concentration at a single time point was used as a surrogate, and the exposure levels aligns with THPP-1’s high permeability and lack of efflux.

(last updated: 12 Oct 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 12 Oct 2020 )