Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

Chauret, Nathalie; Guay, Daniel; Li, Chun; Day, Stephen H.; Silva, José; Blouin, Marc; Ducharme, Yves; Yergey, James A.; Nicoll‐Griffith, Deborah A.

doi:10.1016/s0960-894x(02)00349-9

Cited by 58 publications

(35 citation statements)

References 16 publications

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“…L‐454,560 is a potent and selective inhibitor of PDE4, which was identified as a development candidate for the treatment of such diseases 7. Earlier compounds in the program were extensively metabolized8 or had reactive metabolites leading to high levels of covalent binding 9. The discovery and selection of L‐454,560 (Fig.…”

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confidence: 99%

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

et al. 2006

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L-454,560 is a potent phosphodiesterase 4 (PDE4) inhibitor which was identified as a development candidate for the treatment of asthma and chronic obstructive pulmonary disease (COPD). As part of the discovery of this compound, interspecies in vitro metabolism data was generated using liver microsomes and hepatocytes in order to understand the metabolic fate of the compound. In microsomes, metabolism of the 3-methyl-1,2,4-oxadiazole ring was the predominant pathway observed, including ring cleavage. In rat hepatocytes, hydroxylation of the methyl group on the oxadiazole ring and double-bond isomerization were the most abundant metabolites observed. No major species differences were found in terms of microsomal metabolite profiles. The use of LC with UV and MS detection is highlighted, as well as information from tandem mass spectrometry and NMR.

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Section: Introductionmentioning

confidence: 99%

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

et al. 2006

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“…[1] Aryl difluoromethyl ethers are found in medicinally important compounds that include enzyme inhibitors, [2] anti-HIV agents [3] and atimicrobial agents. [4] Pantoprazole (Protonix®), a proton-pump inhibitor, is among the top 100 pharmaceuticals and contains a difluoromethyl ether.…”

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Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate

2013

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“…Metabolite identification studies are omnipresent throughout the drug discovery and development process 1–3. For example, at the discovery stage, the data is used to identify metabolic soft spots for lead optimization, eliminate compounds that produce potentially reactive metabolites, and generate potential new leads 4, 5. In preclinical development, the selection of toxicology species for safety assessment studies that form all in vitro human metabolites is a common practice 6.…”

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MS^E with mass defect filtering for in vitro and in vivo metabolite identification

Bateman

Castro-Perez

Wrona

et al. 2007

Rapid Comm Mass Spectrometry

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Metabolite identification studies involve the detection and structural characterization of the biotransformation products of drug candidates. These experiments are necessary throughout the drug discovery and development process. The use of high-resolution chromatography and high-resolution mass spectrometry together with data processing using mass defect filtering is described for in vitro and in vivo metabolite identification studies. Data collection was done using UPLC coupled with an orthogonal hybrid quadrupole time-of-flight mass spectrometer. This experimental approach enabled the use of MS(E) data collection (where E represents collision energy) which has previously been shown to be a powerful approach for metabolite identification studies. Post-acquisition processing with a prototype mass defect filtering program was used to eliminate endogenous interferences in the study samples, greatly enhancing the discovery of metabolites. The ease of this approach is illustrated by results showing the detection and structural characterization of metabolites in plasma from a preclinical rat pharmacokinetic study.

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Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

Cited by 58 publications

References 16 publications

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate

MS^E with mass defect filtering for in vitro and in vivo metabolite identification

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Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

Cited by 58 publications

References 16 publications

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

Interspecies in vitro metabolism of the phosphodiesterase‐4 (PDE4) inhibitor L‐454,560

Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate

MSE with mass defect filtering for in vitro and in vivo metabolite identification

Contact Info

Product

Resources

About

MS^E with mass defect filtering for in vitro and in vivo metabolite identification