Epidermal growth factor receptor (EGFR) is a tyrosine kinase with a key role in cell proliferation, death and differentiation. Mutations in EGFR, including substitution of Thr790 by methionine and Leu858 by arginine (T790M/L858R), lead to a lung cancer that is resistant against first generation inhibitors. In fact, second generation inhibitors were developed, but they proved to have had severe side effects because of the significant potency to suppress the wild type protein just as much. To resolve the problem, a step-by-step rational virtual screening was employed over almost sixty million compounds of PubChem Compound Database to filter out selective inhibitor(s) of T790M/L858R subtype. Consequently, the compound CID 133077 was observed, an active metabolite of Axitirome and also a cholesterol lowering prodrug. Selecting this compound can be explained by the oxamic acid part of molecule. Hence, administration of Axitirome or other compounds which contain oxamic acid is suggested in cases with EGFR T790M/L858R drug resistance.

01 Aug 2001·Journal of Chromatography B: Biomedical Sciences and Applications

Quantitative determination of CGS 26214, a cholesterol lowering agent, in human plasma using negative electrospray ionization liquid chromatography–tandem mass spectrometry

Article

Author: Tapan K Majumdar ; Francis L.S Tse ; Shari Wu

CGS 26214 is a synthetic cholesterol-lowering agent shown to be active in the rat, dog and monkey. The present work was conducted to develop a sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for quantitative determination of the compound in human plasma following clinical doses of 10-100 microg per day. A number of analytical challenges were encountered during the development of the assay. The compound was an ester and susceptible to hydrolysis under experimental conditions. A lower limit of quantitation of 50 pg/ml was needed due to the low clinical doses. Positive electrospray ionization of CGS 26214 yielded insufficient sensitivity needed for the studies. Consequently, LC-MS-MS conditions were optimized for the negative ion mode of detection. The sample preparation steps proved to be critical in order to reduce the possibility of microbore column (50 mm x 1.0 mm I.D.) obstruction, chromatographic deterioration, and matrix mediated electrospray ion suppression. The present method addressed the above issues. The method was accurate and reproducible and was successfully applied to generate plasma concentration-time profiles for human subjects after low oral doses of the compound.

01 Sep 2000·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Determination of the chiral isomers of CGS 26214, a synthetic thyromimetic agent, in human plasma using microbore chiral chromatography–tandem mass spectrometry

Q3 · MEDICINE

Article

Author: Tapan K. Majumdar ; Francis L.S. Tse ; David Melamed ; Louis L. Martin

CGS 26214 is a racemic compound having cholesterol-lowering activity in rats, dogs, and monkeys. This compound has two equipotent chiral components CGS 28934(-) and CGS 28935(+). An analytical challenge was to develop a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the analysis of the chiral components in human plasma following clinical doses of 1 mg or less. Several issues had to be addressed in order to devise a LC/MS/MS assay for the above compounds. First, the compounds were esters and susceptible to hydrolysis under experimental conditions. Second, a lower limit of quantitation (LLOQ) of 0.4 ng/ml was needed. Third, positive electrospray ionization of CGS 26214 did not yield sufficient sensitivity needed for the studies in humans. Consequently, LC/MS/MS conditions were optimized for negative ion mode of detection. Fourth, sample preparation steps proved to be critical in order to reduce the possibility of microbore chiral-HPLC column (100 x 1.0 mm i.d.) obstruction, chromatographic deterioration, and matrix mediated electrospray ion suppression. Although the present method addressed the above challenges, its major drawback was limited sample throughput capability. Nonetheless, the method was successfully applied to generate plasma concentration-time profiles for human subjects after oral doses (0.9 mg) of the racemate as well as the optically pure isomers.

100 Deals associated with Axitirome

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D03018	-	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 1	US	-	-
Hyperlipidemias	Phase 1	-	Novartis Pharma AG	-

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