Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 334; no. 1; p. 269
• Main Authors: Lanz, Thomas A, Wood, Kathleen M, Richter, Karl E G, Nolan, Charles E, Becker, Stacey L, Pozdnyakov, Nikolay, Martin, Barbara-Anne, Du, Ping, Oborski, Christine E, Wood, Douglas E, Brown, Tracy M, Finley, James E, Sokolowski, Sharon A, Hicks, Carol D, Coffman, Karen J, Geoghegan, Kieran F, Brodney, Michael A, Liston, Dane, Tate, Barbara
• Format: Journal Article
• Language: English
• Published: United States 01-07-2010
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; Brain - drug effects; Brain - enzymology; Cell Line; Dose-Response Relationship, Drug; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Escherichia coli - genetics; Female; Guinea Pigs; Humans; Lymphocyte Count; Male; Mice; Mice, Inbred Strains; Molecular Structure; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spleen - cytology; Spleen - drug effects; Tetrahydronaphthalenes - adverse effects; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - pharmacokinetics; Tetrahydronaphthalenes - pharmacology; Tissue Distribution; Transfection; Valine - adverse effects; Valine - analogs & derivatives; Valine - chemistry; Valine - pharmacokinetics; Valine - pharmacology
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.167379

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.