RESUMEN
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
Asunto(s)
Pirazoles/síntesis química , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Técnicas In Vitro , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).
Asunto(s)
Bencimidazoles/química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Enlace de Hidrógeno , Concentración 50 Inhibidora , Interleucina-2/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-hck/química , Proteínas Proto-Oncogénicas c-hck/metabolismo , Relación Estructura-ActividadRESUMEN
This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.
Asunto(s)
Industria Farmacéutica/métodos , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Piridazinas/química , Pirimidinas/química , Ribonucleósidos/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Linfocitos/metabolismo , Modelos Químicos , Modelos Moleculares , Piridazinas/farmacología , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).
Asunto(s)
Purinas/química , Factor de Necrosis Tumoral alfa/química , Línea Celular , Química Farmacéutica , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Lipopolisacáridos/química , Modelos Químicos , Modelos Moleculares , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Compuestos de Fenilurea/síntesis química , Pirimidinas/química , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Interleucina-2/biosíntesis , Células Jurkat , Estructura Molecular , Compuestos de Fenilurea/farmacología , RatasRESUMEN
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Asunto(s)
Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Sitios de Unión , Cristalografía por Rayos X , Enlace de Hidrógeno , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/inducido químicamente , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Enlace de Hidrógeno , Yodoacetatos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Osteoartritis/inducido químicamente , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Asunto(s)
Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Pirazolonas/síntesis química , Pirazolonas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Lipopolisacáridos/farmacología , Modelos Moleculares , Conformación Molecular , Osteoartritis/prevención & control , Pirazolonas/química , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Acetaldehído , Sitios de Unión , Línea Celular , Humanos , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pirimidinas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Asunto(s)
Pirazolonas/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Lipopolisacáridos/farmacología , Modelos Moleculares , Pirazolonas/administración & dosificación , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.