RESUMO
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.
Assuntos
Amidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Doença de Alzheimer/tratamento farmacológico , Amidas/metabolismo , Amidas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
We report the synthesis and evaluation of aminoalkylguanidine analogues and derivatives in C57BL/KsJ db/db diabetic mice, following identification by random screening of 1a and 1b as potential antihyperglycemics and/or modulators of food intake. These compounds are related to galegine, a gamma,gamma-dimethylallylguanidine. Between the newly identified compounds, 1h N-(cyclopropylmethyl)- N'-(4-(aminomethyl)cyclohexylmethyl)guanidine showed the most balanced activity as antihyperglycemic and food intake-reducing agent.
Assuntos
Fármacos Antiobesidade/síntese química , Ingestão de Alimentos/efeitos dos fármacos , Guanidinas/síntese química , Hipoglicemiantes/síntese química , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Guanidinas/química , Guanidinas/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Relação Estrutura-AtividadeRESUMO
AIMS: Combined magnetic resonance imaging (MRI) of molecular and morpho-functional changes might prove highly valuable for the elucidation of pathological processes involved in the development of cardiac diseases. Our aim was to test a novel MRI reporter gene for in vivo assessment of the canonical Wnt/ß-catenin/TCF pathway activation, an important regulator of post-ischaemic cardiac remodelling. METHODS AND RESULTS: We designed and developed a chimeric construct encoding for both of iron-binding human ferritin heavy chain (hFTH) controlled by the ß-catenin-responsive TCF/lymphoid-enhancer binding factor (Lef) promoter and constitutively expressed green fluorescent protein (GFP). It was carried by adeno-associated virus serotype 9 (rAAV9) vectors and delivered to the peri-infarct myocardium of rats subjected to coronary ligation (n = 11). By 1.5 T MRI and a multiecho T2* gradient echo sequence, we detected iron accumulation only in the border zone of the transduced infarcted hearts. In the same cardiac area, post-mortem histological analysis confirmed the co-existence of iron accumulation and GFP. The iron signal was absent when rats (n = 6) were chronically treated with SEN195 (10 mg/kg/day), a small-molecular inhibitor of ß-catenin/TCF-dependent gene transcription. Canonical Wnt pathway inhibition attenuated the post-ischaemic remodelling process, as demonstrated by the significant preservation of cardiac function, the 42 ± 1% increase of peri-infarct arteriolar density and 43 ± 3% reduction in infarct scar size compared with untreated animals. CONCLUSIONS: The TCF/Lef promoter-hFTH construct is a novel and reliable MRI reporter gene for in vivo detection of the canonical Wnt/ß-catenin/TCF activation state in response to cardiac injury and therapeutic interventions.