title: Determination of small molecule ABAD inhibitors crossing blood-brain barrier and pharmacokinetics.
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-β peptide with amyloid-β 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 an 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 found to be 0.05 μg/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 that 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 10 mg/kg dose. These results indicate that our newly synthesized small molecule ABAD inhibitors have a good drug properties with the ability to cross the blood-brain barrier, which holds a great potential for AD therapy.
authors.affiliation: Department of Pharmacology & Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Jhansi Rani
authors.initials: JR
authors.lastname: Vangavaragu
authors.affiliation: Department of Pharmacology & Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Koteswara Rao
authors.initials: KR
authors.lastname: Valasani
authors.affiliation: Department of Pharmacology & Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Du
authors.initials: D
authors.lastname: Fang
authors.affiliation: Mass Spectrometry Laboratory University of Kansas, Lawrence, KS, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.affiliation: Department of Pharmacology & Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D051379:Mice; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D015094:3-Hydroxyacyl CoA Dehydrogenases
keywords: ABAD inhibitors; amyloid-β; benzothiazole phosphonates; blood-brain barrier; pharmacokinetics