RESUMEN
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.
Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Hidantoínas/química , Hidantoínas/síntesis química , Hidantoínas/farmacología , Ácidos Pentanoicos/química , Profármacos/síntesis química , Profármacos/farmacología , Proteína ADAM17/metabolismo , Administración Oral , Animales , Área Bajo la Curva , Perros , Activación Enzimática/efectos de los fármacos , Semivida , Haplorrinos , Humanos , Hidantoínas/administración & dosificación , Hidantoínas/farmacocinética , Ácidos Pentanoicos/administración & dosificación , Ácidos Pentanoicos/farmacocinética , Profármacos/administración & dosificación , Profármacos/farmacocinética , Curva ROC , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Hidantoínas/química , Inhibidores de Proteasas/química , Proteína ADAM17/metabolismo , Animales , Área Bajo la Curva , Perros , Activación Enzimática/efectos de los fármacos , Semivida , Haplorrinos , Humanos , Hidantoínas/síntesis química , Hidantoínas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Curva ROC , Ratas , Relación Estructura-ActividadRESUMEN
(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-ß-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/farmacología , Uridina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-Actividad , Uridina/análogos & derivados , Uridina/químicaRESUMEN
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Furanos/química , Hepacivirus/enzimología , Nucleósidos de Pirimidina/química , Pirimidinas/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Benzofuranos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Furanos/síntesis química , Furanos/farmacocinética , Semivida , Hígado/metabolismo , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
Asunto(s)
Antivirales/química , Benzotiazoles/química , Hepacivirus/efectos de los fármacos , Pirimidinas/química , Replicación Viral/efectos de los fármacos , Animales , Perros , Haplorrinos , Hepacivirus/fisiología , Metilación , Roedores , Especificidad de la EspecieRESUMEN
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
The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
Asunto(s)
Antivirales/síntesis química , Carbohidratos/química , Pirimidinas/química , Animales , Antivirales/química , Antivirales/farmacocinética , Disponibilidad Biológica , Perros , Semivida , Haplorrinos , Hepacivirus/efectos de los fármacos , Hepacivirus/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A novel method to synthesize tertiary alkyl/aryl sulfides in a mild and regioselective manner from unactivated alkenes using cobalt catalysis is described. The methodology is compatible with sensitive functionalities and is successful with several different types of alkenes and sulfides.
Asunto(s)
Alquenos/química , Alquenos/síntesis química , Cobalto/química , Sulfuros/química , Sulfuros/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
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
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
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
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tartratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animales , Sitios de Unión , Simulación por Computador , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Tartratos/síntesis química , Tartratos/farmacocinéticaRESUMEN
Novel 2'-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2'-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5'-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
Asunto(s)
Antivirales/síntesis química , Nucleótidos de Guanina/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Alquenos/síntesis química , Azidas/síntesis química , Hepacivirus/enzimología , Proteínas no Estructurales Virales/químicaRESUMEN
We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihydroxamate siderophore-drug conjugates against Candida spp. The conjugated drug was 13C-desketoneoenactin (DE). The MICs of siderophore-drug conjugates were determined in the absence and presence of 2,2'-dipyridyl to restrict iron availability. The ability of various siderophore types to promote growth in an iron-restricted medium was also assayed. Addition of a siderophore portion to the drug strongly impaired the inhibitory activity of DE. However, the activity of the drug conjugates was increased by up to 16-fold in iron-depleted medium for species having their growth strongly promoted by most hydroxamate-type siderophores (C. albicans, C. stellatoidea, and C. pseudotropicalis). The uptake of (55)Fe from ferrichrome and from two siderophore-drug conjugates was improved when C. albicans cells were grown in a low-iron medium. In the same assay, unlabeled ferrichrome was able to compete with the uptake of (55)Fe from both conjugates, indicating a common mechanism of uptake. A C. albicans strain lacking the siderophore transporter CaSit1/CaArn1 was not able to use ferrichrome or the synthetic ornithine-based trihydroxamate siderophore for growth promotion and was much less susceptible to the siderophore-drug conjugates than its isogenic parent strain. In summary, the ability of some Candida spp. to use ferrichrome-like siderophores for growth promotion explains the selective activity of hydroxamate-drug conjugates, and this activity seems to be related to the presence, in C. albicans, of the siderophore transporter CaSit1/CaArn1. New conjugate designs are necessary to fully restore or improve the initial DE activity.