RESUMO
Modulation of γ-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived γ-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of γ-secretase modulators.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Carbazóis/síntese química , Ácidos/síntese química , Ácidos/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/análise , Carbazóis/química , Carbazóis/farmacologia , Ácidos Carboxílicos/análise , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fenofibrato/análogos & derivados , Fenofibrato/química , Humanos , Camundongos , Terapia de Alvo Molecular , Relação Estrutura-AtividadeRESUMO
CK1 and gamma-secretase are interesting targets for therapeutic intervention in the treatment of cancer and Alzheimer's disease. The CK1 inhibitor IC261 was reported to inhibit gamma-secretase activity. The question is: Does CK1 inhibition directly influence gamma-secretase activity? Therefore we analyzed the SAR of 15 analogues and their impact on gamma-secretase activity. The most active compounds were investigated on CK1delta activity. These findings exclude a direct influence of CK1delta on gamma-secretase, because any change in the substitution pattern of IC261 diminished CK1 inhibition, whereas gamma-secretase inhibition is still exerted by several analogues.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Indóis/química , Floroglucinol/análogos & derivados , Inibidores de Proteases/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Caseína Quinase I/metabolismo , Caseína Quinase Idelta/metabolismo , Indóis/farmacologia , Floroglucinol/química , Floroglucinol/farmacologia , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Selective lowering of Abeta(42) levels with small-molecule substrate targeting gamma-secretase modulators (sGSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. Here we present N-substituted carbazole- and O-substituted fenofibrate-derived sGSMs and their activity data. Seven out of 19 screened compounds exhibited promising activity against Abeta(42) secretion at a low micromolar level. We presume that the sGSMs interact with lys624 at the membrane interface and that the lipophilic substituents anchor the compound orientation in the membrane.