RESUMEN
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
RESUMEN
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
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
Asunto(s)
Amidas/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Bazo/enzimología , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Pruebas de Mutagenicidad , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Bazo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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
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 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.
Asunto(s)
Hepacivirus/enzimología , Indoles/farmacología , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Área Bajo la Curva , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Ciclopropanos , Perros , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Indoles/química , Indoles/farmacocinética , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Hígado/metabolismo , Macaca mulatta , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Tasa de Depuración Metabólica , Modelos Químicos , Estructura Molecular , Pan troglodytes , Prolina/análogos & derivados , Ratas , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Sulfonamidas , Proteínas no Estructurales Virales/metabolismo , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/metabolismoRESUMEN
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Asunto(s)
Benzocicloheptenos/síntesis química , Neurotransmisores/síntesis química , Piridinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Benzocicloheptenos/química , Benzocicloheptenos/farmacología , Línea Celular , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmisores/química , Neurotransmisores/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
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
The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Pirimidinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Línea Celular , Perros , Femenino , Lóbulo Frontal/metabolismo , Humanos , Masculino , Dimensión del Dolor , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The synthesis of the first high specific activity S-35-labeled hERG radioligand, [(35)S]MK-0499, for use in HTS assays of drug candidates for hERG interaction is described. The radioligand is prepared by [(35)S]sulfonylation of a high diastereomeric excess (de) aniline precursor prepared from unlabeled MK-0499.
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Piperidinas/química , Piperidinas/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Radiofármacos/síntesis química , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Bloqueadores de los Canales de Potasio/farmacología , Ensayo de Unión Radioligante , Radiofármacos/farmacología , Radioisótopos de Azufre/químicaRESUMEN
Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones having various N-l substituents were identified as potent and selective blockers of the slowly activating cardiac delayed rectifier potassium current (I(Ks)). Compound 11 is the most potent I(Ks) channel blocker reported to date.
Asunto(s)
Antiarrítmicos/síntesis química , Antiarrítmicos/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/efectos de los fármacos , Animales , Antiarrítmicos/metabolismo , Benzodiazepinas/metabolismo , Canales de Potasio de Tipo Rectificador Tardío , Perros , Relación Dosis-Respuesta a Droga , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/metabolismo , Periodo Refractario Electrofisiológico/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A new series of benzodiazepine-containing gamma-secretase inhibitors with potential use in the treatment of Alzheimer's disease is disclosed. Structure-activity relationships of the pendant hydrocinnamate side-chain which led to the preparation of highly potent inhibitors are described.