RESUMEN
Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.
Asunto(s)
Maleimidas/química , Maleimidas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Diabetes Mellitus Experimental/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Maleimidas/farmacocinética , Maleimidas/uso terapéutico , Estructura Molecular , Proteína Quinasa C/metabolismo , Proteína Quinasa C beta , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.
Asunto(s)
Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Isoquinolinas/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Tetrahidroisoquinolinas/síntesis química , Administración Oral , Animales , Arteriopatías Oclusivas/complicaciones , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Infarto Encefálico/patología , Enfermedades Arteriales Cerebrales/complicaciones , Factor Xa/química , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Inyecciones Intravenosas , Isoquinolinas/química , Isoquinolinas/farmacología , Macaca fascicularis , Arteria Cerebral Media , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.
Asunto(s)
Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/farmacología , Tetrahidroisoquinolinas/farmacología , Animales , Ratas , Inhibidores de Serina Proteinasa/uso terapéutico , Tetrahidroisoquinolinas/uso terapéutico , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/enzimologíaRESUMEN
We report herein synthesis of PKCbeta-selective inhibitors possessing the novel pharmacophore of anilino-monoindolylmaleimide. Several compounds of this series exhibited IC50's as low as 50 nM against human PKCbeta2. One of the most potent compounds, 6l, inhibited PKCbeta1 and PKCbeta2 with IC50 of 21 and 5 nM, respectively, and exhibited selectivity of more than 60-fold in favor of PKCbeta2 relative to other PKC isozymes (PKCalpha, PKCgamma, and PKCepsilon).
Asunto(s)
Compuestos de Anilina/síntesis química , Indoles/síntesis química , Maleimidas/síntesis química , Proteína Quinasa C/antagonistas & inhibidores , Compuestos de Anilina/química , Humanos , Indoles/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Maleimidas/química , Proteína Quinasa C/química , Proteína Quinasa C beta , Relación Estructura-ActividadRESUMEN
A series of benzimidazole derivatives with the side chain on the nitrogen atom oriented to the prime site of factor Xa (FXa) were designed and synthesized. Compounds with substituted aminocarbonylmethyl groups as the side chain showed potent FXa inhibitory activity. Compounds 1 and 2 exhibited most potent inhibitory activity and were effective as anticoagulants in a DIC model.