RESUMEN
The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.
Asunto(s)
Benzotiepinas/farmacología , Descubrimiento de Drogas , Trastornos del Humor/tratamiento farmacológico , Receptores de Neuropéptido Y/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Benzotiepinas/síntesis química , Benzotiepinas/química , Disponibilidad Biológica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ratones , Estructura Molecular , Trastornos del Humor/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Asunto(s)
Ftalazinas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Femenino , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos , Ftalazinas/administración & dosificación , Ftalazinas/síntesis química , Piperidinas , Quinazolinas , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
Asunto(s)
Reordenamiento Génico , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/genética , Proteínas Supresoras de Tumor/genética , Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/normas , Salud de la Familia , Femenino , Eliminación de Gen , Humanos , Masculino , Mutación , Linaje , Riñón Poliquístico Autosómico Dominante/diagnóstico , Proteína 2 del Complejo de la Esclerosis TuberosaRESUMEN
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model.
Asunto(s)
Carbanilidas/farmacología , Inhibidores Enzimáticos/farmacología , Glucuronidasa/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Animales , Carbanilidas/síntesis química , Carbanilidas/clasificación , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/clasificación , Técnicas In Vitro , Melanoma Experimental/secundario , Ratones , Estructura Molecular , Peso Molecular , Metástasis de la Neoplasia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice.
Asunto(s)
Benzamidas/farmacología , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glucuronidasa/antagonistas & inhibidores , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Técnicas In Vitro , Ratones , Modelos Animales , Datos de Secuencia Molecular , Estructura Molecular , Peso Molecular , Relación Estructura-ActividadRESUMEN
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Asunto(s)
Isoquinolinas/farmacología , Ftalazinas/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Fluoroinmunoensayo , Humanos , Concentración 50 Inhibidora , Isoquinolinas/síntesis química , Ftalazinas/síntesis química , Relación Estructura-ActividadRESUMEN
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Asunto(s)
Antineoplásicos/síntesis química , Azepinas/síntesis química , Azepinas/farmacología , Receptores ErbB/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Antineoplásicos/farmacología , Azepinas/química , Línea Celular Tumoral , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Concentración 50 Inhibidora , Proteínas de Neoplasias/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Adenosina Trifosfato/metabolismo , Azepinas/química , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
[Reaction: see text]. A synthesis of the title compounds, which have found use as inhibitors of certain receptor tyrosine kinases, was achieved using a Pictet-Spengler cyclization as a key step.
Asunto(s)
Azepinas/química , Azepinas/síntesis química , Catálisis , Ciclización , Estructura MolecularRESUMEN
Pyrimido-oxazepine based sub-micromolar inhibitors (2-4) for Aurora and FLT-3 were designed and synthesized. These preliminary results supported the potential use of pyrimido-oxazepines as a versatile template for developing specific kinase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Oxazepinas/farmacología , Fosfotransferasas/antagonistas & inhibidores , Pirimidinas/farmacología , Aurora Quinasas , Humanos , Cinética , Modelos Moleculares , Oxazepinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Relación Estructura-Actividad , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Ftalazinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Concentración 50 Inhibidora , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Triazoles/química , Triazoles/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Humanos , Microtúbulos/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Moduladores de Tubulina/síntesis química , Células Tumorales CultivadasRESUMEN
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.