RESUMEN
Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms.
Asunto(s)
Proteínas Portadoras/química , Farmacorresistencia Viral , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/química , Antivirales/farmacología , Línea Celular , Clonación Molecular , Cristalografía por Rayos X/métodos , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Rayos XRESUMEN
Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-ßR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.
Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Benzamidas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Receptores de Activinas Tipo I/genética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Femenino , Células HEK293 , Humanos , Masculino , Ratones SCID , Microsomas Hepáticos/metabolismo , Estructura Molecular , Mutación , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Antineoplásicos/farmacología , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Descubrimiento de Drogas , Femenino , Células HEK293 , Humanos , Masculino , Ratones SCID , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Azepinas/síntesis química , Farmacorresistencia Viral , VIH-1/efectos de los fármacos , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Azepinas/química , Azepinas/farmacología , Células CACO-2 , Perros , VIH-1/genética , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Mutación , Permeabilidad , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.
Asunto(s)
Hígado/metabolismo , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
High-throughput screening hit 1 was identified as a potent, broad-spectrum, non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication. Analysis of the bound conformation of analogs of this inhibitor via molecular modeling and NMR contributed to the design of novel tertiary amide, carbamate, and thiocarbamate based NNRTIs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/farmacología , Replicación Viral/efectos de los fármacos , Amidas/química , Fármacos Anti-VIH/síntesis química , Carbamatos/química , Diseño de Fármacos , Farmacorresistencia Viral , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad , Tiocarbamatos/químicaRESUMEN
We have discovered a series of inhibitors of the assembly of the HPV11 E1-E2-origin DNA complex, which incorporate an indandione fused to a substituted tetrahydrofuran.