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Aubry A.-F.,Bristol Myers Squibb | Gu H.,Bristol Myers Squibb | Magnier R.,Atlanbio | Morgan L.,Tandem Laboratories | And 9 more authors.
Bioanalysis | Year: 2010

Background: Dapagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT-2) in development for the treatment of Type 2 diabetes. To support toxicology studies, LC-MS/MS methods were developed and validated for the quantitation of dapagliflozin in rat plasma. Results: The assay uses solid phase extraction and LC-MS/MS analysis in negative ion electrospray ionization mode. Because dapagliflozin readily forms adducts in the presence of formic acid, the mobile phases were simple mixtures of water and acetonitrile. The assay was validated in the concentration range of 5-2000 ng/ml with good intra-and inter-day precisions and acceptable sample stability. Conclusion: The validated assay was successfully applied to the quantitation of dapagliflozin in plasma in support of preclinical studies in both normal and diabetic rats. © 2010 Future Science Ltd.

Woolf E.J.,Merck And Co. | McDougall S.,Covance | Fast D.M.,Covance Laboratories Inc. | Andraus M.,ChromAnalysis | And 27 more authors.
AAPS Journal | Year: 2014

Consensus practices and regulatory guidance for liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays of small molecules are more aligned globally than for any of the other bioanalytical techniques addressed by the Global Bioanalysis Consortium. The three Global Bioanalysis Consortium Harmonization Teams provide recommendations and best practices for areas not yet addressed fully by guidances and consensus for small molecule bioanalysis. Recommendations from all three teams are combined in this report for chromatographic run quality, validation, and sample analysis run acceptance. © 2014 American Association of Pharmaceutical Scientists.

Brewer E.,Tandem Laboratories | Felix T.,Tandem Laboratories | Clarke P.,Pfizer | Edgington A.,Pfizer | Muirhead D.,Pfizer
Biomedical Chromatography | Year: 2010

Maraviroc is a first-in-class CCR5 antagonist that shows potent anti-HIV-1 activity in vitro and in vivo and is well tolerated in both healthy volunteers and HIV-1-infected patients. The method for determination of maraviroc (UK-427,857) and its major metabolite (UK-408,027) in human plasma consists of a protein-precipitation procedure and analysis by liquid chromatography/tandem mass spectrometry using positive ion TurboIonSpray® ionization and multiple reaction monitoring. The assay has been validated over a concentration range of 0.500-500 ng/mL for both analytes. The determinations of maraviroc in human cerebrospinal fluid (0.500-500 ng/mL) and in urine (5.00-5000 ng/mL) have also been validated but do not include measurement of the metabolite. The validations included extraction recovery, intra-assay and inter-assay precision and accuracy, stability of stock and spiking solutions, freeze-thaw stability, matrix stability, processed-extract stability, and evaluation of potential interferences from selected medications in plasma or urine. © 2010 John Wiley & Sons, Ltd.

Toledo-Sherman L.M.,080 Center Drive | Prime M.E.,Evotec | Mrzljak L.,CHDI Management CHDI Foundation | Beconi M.G.,080 Center Drive | And 30 more authors.
Journal of Medicinal Chemistry | Year: 2015

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system. © 2015 American Chemical Society.

Wityak J.,CHDI Foundation Inc. | McGee K.F.,Albany Molecular Research | Conlon M.P.,Albany Molecular Research | Song R.H.,Albany Molecular Research | And 35 more authors.
Journal of Medicinal Chemistry | Year: 2015

Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole. (Chemical Presented) © 2015 American Chemical Society.

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