The synthesis and potent inhibitory activity of novel 4-[(imidazol-1-yl and triazol-1-yl)(phenyl)methyl]aryl-and heteroaryl amines versus a MCF-7 CYP26A1 cell assay is described. Biaryl imidazole ([4-(imidazol-1-yl-phenyl-methyl)-phenyl]-naphthalen-2-yl-amine (8), IC(50)=0.5 microM; [4-(imidazol-1-yl-phenyl-methyl)-phenyl]-indan-5-yl-amine (9), IC(50)=1.0 microM) and heteroaryl imidazole derivatives ((1H-benzoimidazol-2-yl)-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (15), IC(50)=2.5 microM; benzooxazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (16), IC(50)=0.9 microM; benzothiazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (17), IC(50)=1.5 microM) were the most potent CYP26 inhibitors. Using a CYP26A1 homology model differences in activity were investigated. Incubation of SH-SY5Y human neuroblastoma cells with the imidazole aryl derivative 8, and the imidazole heteroaryl derivatives 16 and 17 potentiated the atRA-induced expression of CYP26B1. These data suggest that further structure-function studies leading to clinical development are warranted.
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Background: Retinoid-based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non-specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings.
Objectives: Characterize the therapeutic potential of recently discovered, CYP26-selective RAMBA, DX308.
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Laboratoire de Développement des Gonades, UMR Stabilité Génétique, Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, CEA/DRF/iRCM/SDRR/LDG, 18 route du Panorama, F-92265 Fontenay aux Roses, France.
Article Synopsis
- In female mammals, germ cells start meiosis in the fetal ovaries, while in males, it's delayed until after birth, with retinoic acid (RA) playing a key role in this process.
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- This study shows that while CYP26B1 effectively stops meiosis in female germ cells, RA appears to enhance STRA8 expression rather than directly trigger it, suggesting more complex interactions that should prompt further research into substances that regulate meiosis.
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Department of Oral Biochemistry, Sahlgrenska Academy at the University of Gothenburg, SE-40530 Göteborg, Sweden.
Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the same or adjacent tissues and cells. Yet whether and, if so, how these pathways interact during organogenesis is, to a large extent, unclear.
View Article and Find Full Text PDFInhibition of the Retinoic Acid (RA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous RA Signaling.
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Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (F.S., S.T., N.I.); and School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington (C.H., T.K.)
retinoic acid (RA), the active metabolite of vitamin A, is a ligand for several nuclear receptors and acts as a critical regulator of many physiologic processes. The cytochrome P450 family 26 (CYP26) enzymes are responsible for RA clearance, and are potential drug targets to increase concentrations of endogenous RA in a tissue-specific manner. Talarozole is a potent inhibitor of CYP26A1 and CYP26B1, and has shown some success in clinical trials.
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Department of Pharmaceutics, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Box 357610, Seattle, Washington 98195, United States.
Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed.
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