RESUMEN
A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.
Asunto(s)
Benzofuranos/farmacología , Descubrimiento de Drogas , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Benzofuranos/síntesis química , Benzofuranos/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Estructura Molecular , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ratas , Relación Estructura-ActividadRESUMEN
In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de Receptores de Mineralocorticoides/farmacología , Oxazinas/farmacología , Pirazoles/farmacología , Receptores de Mineralocorticoides/metabolismo , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/química , Antihipertensivos/farmacología , Células COS , Chlorocebus aethiops , Cristalografía por Rayos X , Acetato de Desoxicorticosterona , Relación Dosis-Respuesta a Droga , Humanos , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Masculino , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/química , Modelos Moleculares , Estructura Molecular , Oxazinas/administración & dosificación , Oxazinas/química , Pirazoles/administración & dosificación , Pirazoles/química , Ratas , Ratas Wistar , Receptores de Mineralocorticoides/agonistas , Relación Estructura-ActividadRESUMEN
Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).
Asunto(s)
Benzofuranos/química , Benzoxazinas/química , Diseño de Fármacos , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Pirroles/química , Animales , Células COS , Chlorocebus aethiops , Cristalografía por Rayos X , Concentración 50 Inhibidora , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacología , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Animales , Línea Celular , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Isoquinolinas/química , Proteínas Quinasas JNK Activadas por Mitógenos/química , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model.