RESUMEN
Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Pirimidinas/farmacología , Quinazolinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Pirimidinas/síntesis química , Pirimidinas/química , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/enzimología , Compuestos Macrocíclicos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Proteínas Portadoras/metabolismo , Ciclización , Genotipo , Semivida , Hepacivirus/genética , Péptidos y Proteínas de Señalización Intracelular , Cinética , Hígado/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Quinolinas/química , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/enzimología , Compuestos Macrocíclicos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Sitios de Unión , Proteínas Portadoras/metabolismo , Dominio Catalítico , Ciclización , Genotipo , Semivida , Hepacivirus/genética , Péptidos y Proteínas de Señalización Intracelular , Cinética , Hígado/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
Asunto(s)
Hepacivirus/enzimología , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Ratas , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/químicaRESUMEN
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
Asunto(s)
Antivirales/farmacología , Hepacivirus/enzimología , Compuestos Macrocíclicos/farmacología , Quinazolinonas/farmacología , Sulfonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Cristalografía por Rayos X , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Modelos Moleculares , Mutación , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratas , Sulfonas/farmacocinética , Proteínas no Estructurales Virales/genéticaRESUMEN
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
RESUMEN
The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.
RESUMEN
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.