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Bioorg Med Chem Lett ; 24(24): 5721-5726, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453808


A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/química , Pirróis/química , Administração Oral , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
J Med Chem ; 53(23): 8241-51, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21073190


A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.

Amidas/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Animais , Modelos Moleculares , Ratos
Bioorg Med Chem Lett ; 19(8): 2139-43, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19321341


A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.

Antracenos/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiologia , Relação Estrutura-Atividade