RESUMO
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Tartaratos/química , Proteína ADAM17 , Amidas/síntese química , Amidas/química , Animais , Disponibilidade Biológica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , RatosRESUMO
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteína ADAM17 , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/química , Tartaratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Sítios de Ligação , Simulação por Computador , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/farmacocinéticaRESUMO
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/química , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteases/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Cães , Haplorrinos , Humanos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , RatosRESUMO
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Descoberta de Drogas , Inibidores de Proteases/química , Tartaratos/química , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17 , Sítios de Ligação , Técnicas de Química Combinatória , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Tartaratos/metabolismo , Tartaratos/farmacologiaRESUMO
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Proteína ADAM17 , Inibidores Enzimáticos/química , Hidantoínas/química , Ligação de Hidrogênio , Modelos Moleculares , Relação Estrutura-Atividade , Difração de Raios XRESUMO
A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.
Assuntos
Antivirais/farmacologia , Hepacivirus/enzimologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Modelos Moleculares , Ligação Proteica , Pirazóis/química , Pirimidinas/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
The present paper describes a novel series of HCV RNA polymerase inhibitors based on a pyrazolo[1,5-a]pyrimidine scaffold bearing hydrophobic groups and an acidic functionality. Several compounds were optimized to low nanomolar potencies in a biochemical RdRp assay. SAR trends clearly reveal a stringent preference for a cyclohexyl group as one of the hydrophobes, and improved activities for carboxylic acid derivatives.
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hepatite C/enzimologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Viral/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Hepacivirus , Hepatite C/virologia , Concentração Inibidora 50 , Peso Molecular , Bibliotecas de Moléculas PequenasRESUMO
Aminothiazole-based inhibitors designed for HCV polymerase display low micromolar potencies in biochemical assays. These compounds show a stringent preference for a cyclohexyl hydrophobe at the 2-amino position. The composition of these compounds suggests that they may be interacting at a recently discovered allosteric site on the polymerase.