RESUMEN
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/química , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Dominios Proteicos/efectos de los fármacos , Piridinas/farmacología , Pirroles/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/química , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Elementos de Facilitación Genéticos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Piridinas/efectos adversos , Piridinas/toxicidad , Pirroles/efectos adversos , Pirroles/toxicidad , Ratas , Receptores Androgénicos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.
Asunto(s)
Proteínas Nucleares/antagonistas & inhibidores , Piridonas/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Sitios de Unión , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Ratones , Microsomas/metabolismo , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Estructura Terciaria de Proteína , Piridonas/farmacocinética , Piridonas/farmacología , Piridonas/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
Asunto(s)
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inhibidores , Pirroles/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Semivida , Humanos , Ratones , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (â¼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Descubrimiento de Drogas/métodos , Piridinas/química , Piridinas/metabolismo , Pirroles/química , Pirroles/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Animales , Femenino , Células HeLa , Humanos , Ratones , Ratones SCID , Dominios Proteicos/efectos de los fármacos , Dominios Proteicos/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Piridinas/farmacología , Pirroles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure-activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.
Asunto(s)
Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Benzotiadiazinas/química , Inhibidores Enzimáticos/química , Genotipo , Modelos Moleculares , Estructura Molecular , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Salicilamidas/síntesis química , Salicilamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Estructura Molecular , Salicilamidas/química , Relación Estructura-ActividadRESUMEN
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Hepacivirus/efectos de los fármacos , Pirrolidinas/química , Pirrolidinas/farmacología , Animales , Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Genotipo , Hepacivirus/genética , Hepacivirus/fisiología , Ratones , Pirrolidinas/farmacocinética , Relación Estructura-Actividad , Distribución Tisular , Replicación Viral/efectos de los fármacosRESUMEN
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Asunto(s)
Citosina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Estilbenos/química , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Técnicas de Química Sintética , Citosina/síntesis química , Citosina/química , Citosina/farmacocinética , Citosina/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Permeabilidad , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribución Tisular , Proteínas no Estructurales Virales/químicaRESUMEN
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976-89. ©2017 AACR.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Piridonas/uso terapéutico , Sulfonamidas/uso terapéutico , Antagonistas de Andrógenos/farmacología , Apoptosis , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Piridonas/farmacología , Sulfonamidas/farmacología , TransfecciónRESUMEN
Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 µM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.
Asunto(s)
Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Piridonas/química , Piridonas/farmacología , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas , Compuestos Macrocíclicos/farmacocinética , Estructura Molecular , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9-19-fold. Additional structure-activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.
Asunto(s)
Descubrimiento de Drogas , Proteínas/antagonistas & inhibidores , Piridonas/farmacología , Sulfonamidas/farmacología , Animales , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Transferencia Resonante de Energía de Fluorescencia , Semivida , Humanos , Espectrometría de Masas , Ratones , Espectroscopía de Protones por Resonancia Magnética , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone).
Asunto(s)
Compuestos Alílicos/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Quinolinas/síntesis química , Receptores de Glucocorticoides/efectos de los fármacos , Compuestos Alílicos/química , Compuestos Alílicos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Carragenina , División Celular/efectos de los fármacos , Concanavalina A/farmacología , Selectina E/genética , Selectina E/metabolismo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Técnicas In Vitro , Ligandos , FN-kappa B/metabolismo , Isoformas de Proteínas , Quinolinas/química , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Respuesta , Especificidad de la Especie , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Factor de Transcripción AP-1/metabolismo , Transcripción GenéticaRESUMEN
A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile], a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A-331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A-331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A-331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono- and di-fluorinated analogues (A-417022 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy]-3'-fluoro-1,1'-biphenyl-4-carbonitrile] and A-423579 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-propoxy]-3',5'-difluoro-1,1'-biphenyl-4-carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A-331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A-331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A-417022, in a mouse model of obesity are presented.
Asunto(s)
Fármacos Antiobesidad/farmacología , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Nitrilos/farmacología , Pirrolidinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Línea Celular , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/síntesis química , Ratones , Ratones Endogámicos C57BL , Pruebas de Micronúcleos , Estructura Molecular , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacosRESUMEN
The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
Asunto(s)
Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Animales , Benzotiadiazinas/farmacocinética , Disponibilidad Biológica , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Espectroscopía de Resonancia Magnética , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.
Asunto(s)
Benzotiadiazinas/farmacología , Inhibidores Enzimáticos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Benzotiadiazinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Genotipo , Hidrocarburos Aromáticos/química , Concentración 50 Inhibidora , Naftiridinas/química , Relación Estructura-ActividadRESUMEN
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.
Asunto(s)
Benzotiadiazinas , Inhibidores Enzimáticos , Sulfonamidas , Proteínas no Estructurales Virales/antagonistas & inhibidores , Benzotiadiazinas/síntesis química , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/químicaRESUMEN
N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substituents were significantly more potent than those with benzylic substituents against genotype 1a polymerase. The most potent inhibitors contained small alkyl or carbocyclic substituents and exhibited IC50's of 50-100 and 200-400 nM against genotype 1b and 1a HCV polymerase, respectively.
Asunto(s)
Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Modelos Químicos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
2-aminoethylbenzofurans constitute a new class of H(3) antagonists that are more rotationally constrained than most previously reported H(3) antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/farmacología , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Aminas/química , Animales , Sistema Nervioso Central/efectos de los fármacos , Humanos , Imidazoles/química , Estructura Molecular , Piperidinas/química , Pirroles/química , Pirrolidinas/química , Ratas , Receptores Histamínicos H3/química , Relación Estructura-ActividadRESUMEN
We report the discovery of a novel class of glucocorticoid receptor (GR) antagonists based on the chromene molecular scaffold. The compounds exhibit good functional potency and an improved receptor selectivity profile for GR over other steroid receptors when compared to the classical steroidal GR-antagonist, RU-486.