RESUMEN
The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.
Asunto(s)
Descubrimiento de Drogas , Factor IXa/antagonistas & inhibidores , Inhibidores del Factor Xa/farmacología , Pirimidinas/farmacología , Relación Dosis-Respuesta a Droga , Factor IXa/metabolismo , Inhibidores del Factor Xa/síntesis química , Inhibidores del Factor Xa/química , Humanos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.
RESUMEN
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 µM), highly selective, and safe in in vitro and in vivo assays.
Asunto(s)
Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Indoles/química , Quinolinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Masculino , Simulación de Dinámica Molecular , Unión Proteica , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas no Estructurales Virales/metabolismoRESUMEN
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oxazoles/farmacología , Triglicéridos/sangre , Animales , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 µM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Indoles/síntesis química , Nitrocompuestos/síntesis química , Sulfonas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Cristalografía por Rayos X , Perros , Haplorrinos , Hepacivirus/enzimología , Indoles/farmacocinética , Indoles/farmacología , Modelos Moleculares , Estructura Molecular , Pruebas de Mutagenicidad , Nitrocompuestos/farmacocinética , Nitrocompuestos/farmacología , Piridonas/síntesis química , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/farmacocinética , Sulfonas/farmacologíaRESUMEN
A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.
RESUMEN
Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 µM) and cell-based replicon (EC(50) = 0.02 µM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 µM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/enzimología , Indoles/síntesis química , Sulfonamidas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Células CACO-2 , Cristalografía por Rayos X , Perros , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Humanos , Indoles/química , Indoles/farmacocinética , Indoles/farmacología , Modelos Moleculares , Estructura Molecular , Permeabilidad , Ratas , Replicón , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053µM, replicon EC(50)=4.8µM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039µM, replicon EC(50)=0.011µM) with >100-fold improved replicon activity.
Asunto(s)
Antivirales/farmacología , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 µM, replicon EC(50)>100 µM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 µM, replicon EC(50)=1.4 µM) and 7r (NS5B IC(50)=0.017 µM, replicon EC(50)=0.3 µM) with improved enzyme and replicon activity.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Indoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ácidos Carboxílicos , Dominio Catalítico/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
An affinity-selection study using size exclusion chromatography (SEC) combined with off-line electrospray ionization mass spectrometry (ESI-MS) was performed on libraries of peptidic α-ketoamide inhibitors directed against the hepatitis C virus (HCV) NS3 protease. A limiting amount of HCV NS3 protease (25 µM) was incubated with equimolar amounts (100 µM) of 49 reversible mechanism-based ketoamide inhibitors, previously grouped into seven sets to ensure clearly distinguishable mass differences of the enzyme-inhibitor complexes (>10 Da). The unbound compounds were separated rapidly from the protease and the protease-inhibitor complexes by SEC spin columns. The eluate of the SEC was immediately analyzed by direct-infusion ESI-MS. An enzyme-inhibitor complex, with a molecular mass corresponding to the NS3 protease binding to the preferred inhibitor, SCH212986, was the only molecular species detected. By increasing the molar ratio of HCV NS3 protease to inhibitors to 1:2 while keeping the inhibitors' concentration constant, the complex of the second most tightly bound inhibitor, SCH215426, was also identified. Although the potencies of these inhibitors were virtually un-measurable by kinetic assays, a rank order of CVS4441 > SCH212986 > SCH215426 was deduced for their inhibition potencies by direct competition experiment with CVS4441 (K(i)*>80 µM). As discussed in the article, through judicious application of this strategy, even large libraries of fairly weak, reversible and slow-binding inhibitors could be rapidly screened and rank ordered to provide critical initial structure-activity insights.
Asunto(s)
Inhibidores de Proteasas/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Proteínas no Estructurales Virales/química , Amidas/química , Amidas/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Cromatografía en Gel , Descubrimiento de Drogas/métodos , Estabilidad de Enzimas , Holoenzimas/química , Holoenzimas/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Inhibidores de Proteasas/metabolismo , Unión Proteica , Proteínas no Estructurales Virales/metabolismoRESUMEN
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
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
RESUMEN
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Asunto(s)
Fármacos Antidiuréticos/química , Antagonistas de los Receptores de Hormonas Antidiuréticas , Quinolinas/química , Sulfonamidas/química , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/farmacología , Humanos , Quinolinas/síntesis química , Quinolinas/farmacología , Ratas , Receptores de Oxitocina/antagonistas & inhibidores , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.