PF-04802367

F-04802367 (PF-367) is a highly selective GSK-3 inhibitor with an IC50 of 2.1 nM based on a recombinant human GSK-3β enzyme assay and 1.1 nM based on ADP-Glo assay. PF-04802367 shows desirable central nervous system (CNS) properties and potency. PF-04802367 is equally effective at inhibition of the two known GSK-3 isoforms (GSK-3α and GSK-3β) with IC50 values of 10.0 and 9.0 nM in mobility shift assays, respectively.

Product information

CAS Number: 1962178-27-3

Molecular Weight: 361.78

Formula: C16H16ClN5O3

Chemical Name: 4-(3-chloro-4-methoxyphenyl)-N-[3-(1H-1, 2, 4-triazol-1-yl)propyl]-1, 3-oxazole-5-carboxamide

Smiles: COC1=CC=C(C=C1Cl)C1N=COC=1C(=O)NCCCN1C=NC=N1

InChiKey: VQZHXGWCLUVZQI-UHFFFAOYSA-N

InChi: InChI=1S/C16H16ClN5O3/c1-24-13-4-3-11(7-12(13)17)14-15(25-10-20-14)16(23)19-5-2-6-22-9-18-8-21-22/h3-4,7-10H,2,5-6H2,1H3,(H,19,23)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: To be determined

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

PF-04802367 (PF-367) is efficient at inhibiting GSK-3β enzymatic activity in vitro with ligand and lipophilic efficiency scores of 0.46 and 7.0, respectively. PF-367 has reasonable in vitro stability in human hepatic microsomes (t1/2=78.7 min), has excellent passive permeability. In a stable inducible CHO cell line over-expressing GSK-3β and its substrate tau, PF-367 inhibited phosphorylation of tau with an IC50 of 466 nM. PF-367 has good cell viability (IC50 of 117 μM in THLE cytotoxicity assays) and an IC50 >100 μM in a hERG screening assay. PF-367 shows significant right shifts against β-catenin translocation in HeLa cells with EC50 of 6.2 μM, gene transcription in U20S cells with EC50 of 20.6 μM, and cell proliferation in HeLa cells as evaluated by Ki-67 incorporation with EC50 of 9.0 μM.

In Vivo:

PF-04802367 (PF-367) a potent GSK-3 inhibitor with exceptional kinome selectivity that modulates phosphorylated tau levels in vivo. Inhibition of phosphorylation of tau in brain by PF-367 (A single subcutaneous of 1, 3.2, 10, 32 or 50 mg/kg) is dose-dependent. PF-04802367 (PF-367), a potent type-I dual GSK-3α/β inhibitor, showing promising absorption; distribution, metabolism and elimination (ADME) properties combined with robust CNS/peripheral p-Tau and muscle phosphorylated glycogen synthase (pGS) inhibition in vivo.

References:

1. Vadim Bernard-Gauthier, et al. Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery. J Med Chem. 2019 Nov 14;62(21):9600-9617.
2. Steven H Liang, et al. Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Angew Chem Int Ed Engl. 2016 Aug 8;55(33):9601-5.

Products are for research use only. Not for human use.