"目录号: HY-14531

Metabolic Enzyme/Protease-

Talarozole 是一种有效的CYP26A1和CYP26B1抑制剂，IC50分别为 5.1 nM 和 0.46 nM。

Cytochrome P450

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生物活性

Description

Talarozole is a potent inhibitor of bothCYP26A1andCYP26B1, withIC50of 0.46 nM and 5.1 nM forCYP26B1andCYP26A1, respectively.

IC50& Target

IC50: 0.46/5.1 nM (CYP26B1/A1)[1]

In Vitro

When HepG2 cells are cotreated with atRA and Talarozole (1 μM), 4-OH-RA and 4-oxo-RA formation is significantly decreased[2].

In Vivo

A maximum 84% inhibition of CYP26 activity at 0.5 hours post-dose is predicted based on Talarozole (TLZ) Cmaxof 80 nM and a Kiof 1 nM following a single dose of Talarozole. Due to the short Talarozole half-life (2.2 hrs) CYP26 activity is predicted to return to 100% by 12 hours. In agreement with the predictions,atRA concentrations are increased by 82, 63 and 60% at 4 hours post-dose in the serum, liver and testes, respectively, and concentrations returned to baseline by 24 hours. Following multiple doses of Talarozole, liver CYP26 mRNA and activity are increased suggesting autoinduction of CYP26 due to increasedatRA concentrations. In agreement,atRA concentrations are elevated in serum and liver at all timepoints measured. This increase inatRA concentrations is associated with increased mRNA of the mitochondrial biogenesis markers PGC-1β and NRF-1 in comparison to control mice[3].

Clinical Trial

NCT00725439

Stiefel, a GSK Company-GlaxoSmithKline

Acne

September 2004

Phase 2

NCT00716144

Stiefel, a GSK Company-GlaxoSmithKline

Psoriasis

June 2006

Phase 2

NCT00719121

Stiefel, a GSK Company-GlaxoSmithKline

Cutaneous Inflammation

November 2006

Phase 1

NCT00725348

Stiefel, a GSK Company-GlaxoSmithKline

Psoriasis

April 2004

Phase 2

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References

[1].Diaz P, et al. Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, theHuman Liver Retinoic Acid Hydroxylase. J Med Chem. 2016 Mar 24;59(6):2579-95.

[2].Topletz AR, et al. Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in theelimination of active retinoids. Mol Pharmacol. 2015;87(3):430-41.

[3].Faith Stevison, et al. CYP26 Inhibition Increases Retinoic Acid Concentrations in Target Tissues and Alters Retinoid Signaling

[4].Tripathy S, et al.All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver. Mol Pharmacol. 2016 May;89(5):560-74.