RESUMEN
Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/farmacocinética , Perros , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirrolidinas/química , Tartratos/química , Proteína ADAM17 , Amidas/síntesis química , Amidas/química , Animales , Disponibilidad Biológica , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , RatasRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hidantoínas/farmacología , Proteína ADAM17 , Inhibidores Enzimáticos/química , Hidantoínas/química , Enlace de Hidrógeno , Modelos Moleculares , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Descubrimiento de Drogas , Inhibidores de Proteasas/química , Tartratos/química , Factor de Necrosis Tumoral alfa/metabolismo , Proteína ADAM17 , Sitios de Unión , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Humanos , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Tartratos/metabolismo , Tartratos/farmacologíaRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Antiinflamatorios/química , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de Proteasas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Perros , Haplorrinos , Humanos , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , RatasRESUMEN
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.