ABSTRACT
The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a ß-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aß in guinea pigs. The therapeutic index between Aß reductions and changes in B-cell populations were studied for compound 10 h.
Subject(s)
Alzheimer Disease , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Amination/drug effects , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/metabolism , Animals , Biological Assay , Diamide/chemical synthesis , Diamide/chemistry , Diamide/pharmacology , Enzyme Inhibitors/chemistry , Guinea Pigs , HeLa Cells , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aß in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aß EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Valine/analogs & derivatives , Animals , Biological Assay , Drug Design , Enzyme Inhibitors/chemistry , Guinea Pigs , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacologyABSTRACT
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.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Tetrahydronaphthalenes/pharmacology , Tetrahydronaphthalenes/pharmacokinetics , Valine/analogs & derivatives , 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 , 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 , Tissue Distribution , Transfection , Valine/adverse effects , Valine/chemistry , Valine/pharmacokinetics , Valine/pharmacologyABSTRACT
The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described.
