| Novel Cytochrome P450-mediated Ring Opening of the 1,3,4-oxadiazole in Setileuton, a 5-lipoxygenase inhibitor. | |
| | |
MedLine Citation:
|
PMID: 21325431 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Setileuton (4-(4-fluorophenyl)-7-[({5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-1-benzopyran-2-one) is a selective inhibitor of the 5-lipoxygenase enzyme, which is under investigation for the treatment of asthma and atherosclerosis. During the development of setileuton, a metabolite (M5) was identified in incubations with rat, dog, and human liver microsomes which represented the addition of 18 Daltons to the 1,3,4-oxadiazole portion of the molecule. Based on mass spectral data, a ring opened structure was proposed and confirmed through comparison with a synthetic standard. The metabolic ring opening was examined in vitro in rat liver microsomes and determined to be mediated by cytochrome P450s. Upon examination of the specific cytochrome P450s involved using cDNA expressed rat P450s, it was shown that CYP1A2 likely was the major isoform contributing to the formation of M5. Studies utilizing stable labeled molecular oxygen and water demonstrated that the oxygen was incorporated from molecular oxygen, rather than water, and confirmed that the metabolic formation was oxidative. An alternative, comparatively slow, pathway of chemical hydrolysis also was identified and described. Three potential mechanisms for the two-step metabolic ring opening of the 1,3,4-oxadizole are proposed. |
| | |
Authors:
|
Cheri M Maciolek; Bennett Ma; Karsten Menzel; Sebastien Laliberte; Kevin Bateman; Paul Krolikowski; Christopher R Gibson |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2011-2-16 |
Journal Detail:
|
Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 Feb |
Date Detail:
|
Created Date: 2011-2-17 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
1 Merck & Co. Inc; |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Evaluation of the Effects of 20 Non-synonymous Single-nucleotide Polymorphisms of CYP2C19 on S-Mephe...
Next Document: Organic anion transporter 3 mediates the efflux transport of an amphipathic organic anion, dehydroep...