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
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Hepatitis C/tratamiento farmacológico , Imidazoles/síntesis química , Imidazoles/química , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Asunto(s)
Antivirales/química , Hepacivirus/metabolismo , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/metabolismo , Antivirales/farmacología , Área Bajo la Curva , Genotipo , Semivida , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Indoles/metabolismo , Indoles/farmacología , Curva ROC , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Imidazoles/farmacología , Indoles/química , Prolina/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Benzofuranos/química , Imidazoles/química , Relación Estructura-ActividadRESUMEN
The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.
Asunto(s)
Piperazinas/química , Pirazinas/química , Receptores CXCR3/antagonistas & inhibidores , Animales , Concentración 50 Inhibidora , Estructura Molecular , Piperazinas/farmacología , Unión Proteica/efectos de los fármacos , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Asunto(s)
Receptor Cannabinoide CB2/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonas/química , Sulfonas/síntesis química , Animales , Canales de Calcio/metabolismo , Sistema Enzimático del Citocromo P-450 , Agonismo Inverso de Drogas , Humanos , Piperidinas/química , Ratas , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/farmacocinéticaRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteína ADAM17 , Animales , Ratas , Relación Estructura-ActividadRESUMEN
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
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Asunto(s)
Química Farmacéutica/métodos , Receptor Cannabinoide CB2/química , Sulfonas/química , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cinética , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Receptores de Droga , Sodio/química , Relación Estructura-ActividadRESUMEN
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.