ITI-214

ITI-214 : Inhibitor of PDE1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

PDE1A
PDE1B
PDE1C

Inhibitor

100 nM
Reviewer recommended concentration: Reviewer recommends 3 or 6mpk for in vivo use based on available data.

Probe Availability:

In Vitro Validations

Uniprot ID: P54750

Target Class: Enzyme

Target SubClass: Phosphodiesterase

Potency: Ki

Potency Value: 0.058 nM

Potency Assay: Enzymatic assay with fluorescent-labeled cAMP

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Calcium/calmodulin-dependent 3',5'-cyclic nucleoti ...

DOI Reference: 10.1021/acs.jmedchem.5b01751

In Cell Validations

No in Cell Validations available

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

PDE Family Selectivity in Ki (UM): PDE1 0.000058 PDE2A 18 PDE3B 3.1 PDE4A 0.16 PDE5A 0.63 PDE6 0.32 PDE7B 0.36 PDE8A 3.0 PDE9A 17 PDE10A 1.8 PDE11A 1.3 ITI-214 was assayed for potential off-target interactions against a standard panel of key proteins, including neurotransmitter receptors, ion channels, ion pumps, synthetic enzymes, and transporter proteins. This 70-target diversity panel [Side Effect Profile (SEP) II, Caliper Life Sciences], performed at a drug concentration of 10 μM, or roughly 300,000-fold in excess of the K i of ITI-214 for inhibition of the PDE1A isoform, identified only 4 substrates showing >50 % binding to ITI-214, including Na+ channel (site 2), Ca2+ channel (L, DHP site), NK3, neurokinin receptor, and the dopamine transporter.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

ITI-214 is one of the best compounds for evaluating the inhibitory effect of PDE1 in vivo.

(last updated: 12 Jun 2022 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

The probe molecule was extensively tested in vitro and in vivo PK studies have been provided. Moreover, in vivo data is presented in the respective animals.

(last updated: 13 Jun 2022 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

ITI-214 is a clinical candidate targeting phosphodiesterase 1 isoforms. While extensive enzymatic assay characterization is provided for ITI-214 and a wide range of analogs, no cellular assay data is provided, precluding any recommendation regarding cell-based use. Additionally, strong selectivity vs 10 other PDE enzymes was demonstrated, but the relatively high log D of this probe (4.4) nonetheless suggests potential for off-target effects. PK studies in both mouse (PO) and rat (IV/PO) are provided and establish that ITI-214 has a meaningful half-life (ca 1.5h) and brain-to-plasma ratio (Kp 0.7) that support this probe's use in vivo, including in the CNS. However, no data is provided regarding plasma protein binding and no assessment of Kp(u,u) is provided. Additionally, only one rat efficacy model is described which showed a U-shaped dose response (expected in the model, apparently), with efficacy shown at 3 and 6 mpk but not 1 or 10 mpk. This result creates ambiguity about recommending doses for in vivo use, as 10mpk or higher doses may be efficacious in other models. If data from other models is subsequently published (as stated in the text), recommended doses may need to be revised and this probe may warrant a 4-star rating.

(last updated: 26 Sept 2022 )