RESUMEN
Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S1, S2 and S1' subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50â¯=â¯0.38⯵M; BACE-1 WCA IC50â¯=â¯0.14⯵M) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50â¯=â¯0.49⯵M; BACE-1 WCA IC50â¯=â¯0.14⯵M) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S2 subsite.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Conformación Molecular , Quinazolinas/síntesis química , Quinazolinas/farmacología , Relación Estructura-ActividadAsunto(s)
Infecciones por Coronavirus , Coronavirus , Betacoronavirus , COVID-19 , Humanos , Pandemias , Neumonía Viral , SARS-CoV-2 , Taiwán , Tomografía Computarizada por Rayos XRESUMEN
Despite embolization being now considered the preferred treatment for PAVM, surgical intervention may be considered if the malformation involves large vessels.
RESUMEN
We demonstrate that the acrylamide group can be used to improve the drug-like properties of potential drug candidates. In the EGFR inhibitor development, both the solubility and membrane permeability properties of compounds 6a and 7, each containing an acrylamide group, were substantially better than those of gefitinib (1) and AZD3759 (2), respectively. We demonstrated that incorporation of an acrylamide moiety could serve as a good strategy for improving drug-like properties.