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Determination of Small Molecule ABAD Inhibitors Crossing Blood Brain Barrier and Pharmacokinetics
Vangavaragu, Jhansi Rani Valasani, Koteswara Rao Du, Fang Williams, Todd D. Yan, Shirley ShiDu
Vangavaragu, Jhansi Rani
Valasani, Koteswara Rao
Du, Fang
Williams, Todd D.
Yan, Shirley ShiDu
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Abstract
A major obstacle to the development of effective treatment of Alzheimer’s disease (AD) is successfully delivery of drugs to the brain. We have previously identified a series of benzothiazole phosphonate compounds that block the interaction of amyloid beta peptide (Aβ) with amyloid-beta binding alcohol dehydrogenase (ABAD). A selective and sensitive method for the presence of three new benzothiazole ABAD inhibitors in mouse plasma, brain and artificial cerebrospinal fluid has been developed and validated based on high performance liquid chromatography tandem mass spectrometry. Mass spectra were generated using Micromass Quattro Ultima “triple” quadrupole mass spectrometer equipped with Electrospray ionization interface. Good linearity was obtained over a concentration range of 0.05–2.5 µg/ml. The lowest limit of quantification and detection was 0.05µg/ml. All inter-day accuracies and precisions were within ±15% of the nominal value and ±20%, respectively, at the lower limit of quantitation. The tested compounds were stable at various conditions with recoveries >90.0 % (RSD<10%). The method used for pharmacokinetic studies of compounds in mouse cerebrospinal fluid, plasma, and brain is accurate, precise, and specific with no matrix effect. Pharmacokinetic data showed these compounds penetrate the blood–brain barrier (BBB) yielding 4–50 ng/ml peak brain concentrations and 2 µg/ml peak plasma concentrations from a 10mg/kg dose. These results indicate that our newly synthesized small molecule ABAD inhibitor have good drug properties with the ability to cross the blood brain barrier, which holds a great potential for AD therapy.
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Date
2014-04-02
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IOS Press
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Keywords
ABAD inhibitors, Amyloid-β, Benzothiazole phosphonates, Blood-brain barrier pharmacokinetics
Citation
Vangavaragu, Jhansi Rani, Koteswara Rao Valasani, Du Fang, Todd D. Williams, and Shirley ShiDu Yan. "Determination of Small Molecule ABAD Inhibitors Crossing Blood Brain Barrier and Pharmacokinetics." Journal of Alzheimer's Disease 42 (2014): 333-44.