RESUMO
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/síntese química , Hidantoínas/farmacologia , Ácidos Pentanoicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Proteína ADAM17/metabolismo , Administração Oral , Animais , Área Sob a Curva , Cães , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Hidantoínas/administração & dosagem , Hidantoínas/farmacocinética , Ácidos Pentanoicos/administração & dosagem , Ácidos Pentanoicos/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Curva ROC , Ratos , Relação Estrutura-AtividadeRESUMO
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Hidantoínas/química , Inibidores de Proteases/química , Proteína ADAM17/metabolismo , Animais , Área Sob a Curva , Cães , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Hidantoínas/síntese química , Hidantoínas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Curva ROC , Ratos , Relação Estrutura-AtividadeRESUMO
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
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.