RESUMO
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.
Assuntos
Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Pirazolonas/síntese química , Pirazolonas/farmacologia , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Cinética , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Conformação Molecular , Osteoartrite/prevenção & controle , Pirazolonas/química , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
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.
Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Pirimidinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Acetaldeído , Sítios de Ligação , Linhagem Celular , Humanos , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Pirazóis/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Pirazóis/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
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.
Assuntos
Pirazolonas/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Pirazolonas/administração & dosagem , Pirazolonas/farmacocinética , Pirazolonas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Pirazóis/síntese química , Pirimidinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
[reaction: see text] Iridium-catalyzed reductive coupling of acrylates and imines provides trans beta-lactams with high diastereoselection. The optimal catalyst allows for the synthesis of trans beta-lactams bearing aromatic, alkenyl, and alkynyl side chains. This reaction appears to proceed through a reductive Mannich addition-cyclization mechanism. Examination of substituent effects reveals a linear Hammett correlation for both the N-aryl group on the imine and the aryloxy group on the acrylate, thereby pointing to rate-determining cyclization in the reaction mechanism.
