RESUMO
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.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Aminação/efeitos dos fármacos , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/metabolismo , Animais , Bioensaio , Diamida/síntese química , Diamida/química , Diamida/farmacologia , Inibidores Enzimáticos/química , Cobaias , Células HeLa , Humanos , Imidazóis/química , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Valina/análogos & derivados , Animais , Bioensaio , Desenho de Fármacos , Inibidores Enzimáticos/química , Cobaias , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Valina/síntese química , Valina/química , Valina/farmacologiaRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/farmacocinética , Valina/análogos & derivados , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Escherichia coli/genética , Feminino , Cobaias , Humanos , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Baço/citologia , Baço/efeitos dos fármacos , Tetra-Hidronaftalenos/efeitos adversos , Tetra-Hidronaftalenos/química , Distribuição Tecidual , Transfecção , Valina/efeitos adversos , Valina/química , Valina/farmacocinética , Valina/farmacologiaRESUMO
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.