Pharmacodynamics and Pharmacokinetics of the γ-Secretase Inhibitor PF-3084014
| Autor: | Kathleen M. Wood, Ping Du, Karen J. Coffman, Karl E.G. Richter, Sharon A. Sokolowski, Barbara-Anne Martin, Dane R. Liston, Barbara Tate, Douglas E. Wood, Tracy M. Brown, Michael Aaron Brodney, Carol D. Hicks, Charles E. Nolan, Nikolay Pozdnyakov, James E. Finley, Christine E. Oborski, Stacey L. Becker, Thomas A. Lanz, Kieran F. Geoghegan |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Tetrahydronaphthalenes Guinea Pigs Mice Inbred Strains Pharmacology Transfection Cell Line Mice Cerebrospinal fluid Therapeutic index Pharmacokinetics In vivo mental disorders Escherichia coli Animals Humans Potency Tissue Distribution Lymphocyte Count Enzyme Inhibitors Gamma secretase B-Lymphocytes Dose-Response Relationship Drug Molecular Structure Chemistry Brain Valine In vitro Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Pharmacodynamics Molecular Medicine Female Amyloid Precursor Protein Secretases Spleen |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 334:269-277 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | PF-3084014 [(S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide] is a novel gamma-secretase inhibitor that reduces amyloid-beta (Abeta) production with an in vitro IC(50) of 1.2 nM (whole-cell assay) to 6.2 nM (cell-free assay). This compound inhibits Notch-related T- and B-cell maturation in an in vitro thymocyte assay with an EC(50) of 2.1 microM. A single acute dose showed dose-dependent reduction in brain, cerebrospinal fluid (CSF), and plasma Abeta in Tg2576 mice as measured by enzyme-linked immunosorbent assay and immunoprecipitation (IP)/mass spectrometry (MS). Guinea pigs were dosed with PF-3084014 for 5 days via osmotic minipump at 0.03 to 3 mg/kg/day and exhibited dose-dependent reduction in brain, CSF, and plasma Abeta. To further characterize Abeta dynamics in brain, CSF, and plasma in relation to drug exposure and Notch-related toxicities, guinea pigs were dosed with 0.03 to 10 mg/kg PF-3084014, and tissues were collected at regular intervals from 0.75 to 30 h after dose. Brain, CSF, and plasma all exhibited dose-dependent reductions in Abeta, and the magnitude and duration of Abeta lowering exceeded those of the reductions in B-cell endpoints. Other gamma-secretase inhibitors have shown high potency at elevating Abeta in the conditioned media of whole cells and the plasma of multiple animal models and humans. Such potentiation was not observed with PF-3084014. IP/MS analysis, however, revealed dose-dependent increases in Abeta11-40 and Abeta1-43 at doses that potently inhibited Abeta1-40 and Abeta1-42. PF-3084014, like previously described gamma-secretase inhibitors, preferentially reduced Abeta1-40 relative to Abeta1-42. Potency at Abeta relative to Notch-related endpoints in vitro and in vivo suggests that a therapeutic index can be achieved with this compound. |
| Databáze: | OpenAIRE |
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