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A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2015 Jun; Vol. 43 (6), pp. 908-15. Date of Electronic Publication: 2015 Apr 06. - Publication Year :
- 2015
-
Abstract
- GDC-0834, a Bruton's tyrosine kinase inhibitor investigated as a potential treatment of rheumatoid arthritis, was previously reported to be extensively metabolized by amide hydrolysis such that no measurable levels of this compound were detected in human circulation after oral administration. In vitro studies in human liver cytosol determined that GDC-0834 (R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxamide) was rapidly hydrolyzed with a CLint of 0.511 ml/min per milligram of protein. Aldehyde oxidase (AO) and carboxylesterase (CES) were putatively identified as the enzymes responsible after cytosolic fractionation and mass spectrometry-proteomics analysis of the enzymatically active fractions. Results were confirmed by a series of kinetic experiments with inhibitors of AO, CES, and xanthine oxidase (XO), which implicated AO and CES, but not XO, as mediating GDC-0834 amide hydrolysis. Further supporting the interaction between GDC-0834 and AO, GDC-0834 was shown to be a potent reversible inhibitor of six known AO substrates with IC50 values ranging from 0.86 to 1.87 μM. Additionally, in silico modeling studies suggest that GDC-0834 is capable of binding in the active site of AO with the amide bond of GDC-0834 near the molybdenum cofactor (MoCo), orientated in such a way to enable potential nucleophilic attack on the carbonyl of the amide bond by the hydroxyl of MoCo. Together, the in vitro and in silico results suggest the involvement of AO in the amide hydrolysis of GDC-0834.<br /> (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Agammaglobulinaemia Tyrosine Kinase
Aldehyde Oxidase chemistry
Animals
Anti-Inflammatory Agents, Non-Steroidal blood
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics
Biocatalysis
Catalytic Domain
Cytosol enzymology
Cytosol metabolism
Drug Stability
Drugs, Investigational analysis
Drugs, Investigational chemistry
Drugs, Investigational pharmacokinetics
Gene Expression Profiling
Humans
Hydrolysis
Kinetics
Liver enzymology
Liver metabolism
Molecular Conformation
Molecular Docking Simulation
Protein Kinase Inhibitors blood
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacokinetics
Protein-Tyrosine Kinases chemistry
Protein-Tyrosine Kinases metabolism
Pyrimidinones blood
Pyrimidinones chemistry
Pyrimidinones pharmacokinetics
Substrate Specificity
Thiophenes blood
Thiophenes chemistry
Thiophenes pharmacokinetics
Aldehyde Oxidase metabolism
Anti-Inflammatory Agents, Non-Steroidal metabolism
Drugs, Investigational metabolism
Models, Molecular
Protein Kinase Inhibitors metabolism
Protein-Tyrosine Kinases antagonists & inhibitors
Pyrimidinones metabolism
Thiophenes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 43
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 25845827
- Full Text :
- https://doi.org/10.1124/dmd.114.061804