RESUMEN
Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).
Asunto(s)
Metionina Adenosiltransferasa , Neoplasias , Encéfalo/metabolismo , Diseño de Fármacos , Humanos , Neoplasias/tratamiento farmacológico , S-Adenosilmetionina/metabolismoRESUMEN
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10â¯000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
Asunto(s)
Inhibidores Enzimáticos/química , Metionina Adenosiltransferasa/antagonistas & inhibidores , Purina-Nucleósido Fosforilasa/genética , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Homocigoto , Humanos , Metionina Adenosiltransferasa/metabolismo , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Purina-Nucleósido Fosforilasa/metabolismo , S-Adenosilmetionina/metabolismo , Relación Estructura-ActividadRESUMEN
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.
Asunto(s)
Daño del ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Metionina Adenosiltransferasa/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/genética , Purina-Nucleósido Fosforilasa/genética , Empalme del ARN/efectos de los fármacos , ARN Mensajero/genética , Animales , Línea Celular , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Daño del ADN/genética , Eliminación de Gen , Células HCT116 , Células HEK293 , Humanos , Metionina Adenosiltransferasa/genética , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Empalme del ARN/genética , S-Adenosilmetionina/metabolismoRESUMEN
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.
RESUMEN
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.
Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Triazinas/farmacología , Animales , Línea Celular Tumoral , Humanos , Isocitrato Deshidrogenasa/genética , Ratones , Mutación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2 Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494-505. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Yen et al., p. 478This article is highlighted in the In This Issue feature, p. 443.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Unión al ADN/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Proteínas Proto-Oncogénicas/genética , Aminopiridinas/farmacología , Animales , Azacitidina/farmacología , Metilación de ADN/efectos de los fármacos , Dioxigenasas , Epigénesis Genética/efectos de los fármacos , Leucemia Mieloide Aguda/genética , Ratones , Ratones Mutantes , Mutación , Transducción de Señal/efectos de los fármacos , Triazinas/farmacología , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.
Asunto(s)
Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Cardiomiopatías/tratamiento farmacológico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Mutación/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Encefalopatías Metabólicas Innatas/genética , Modelos Animales de Enfermedad , Isocitrato Deshidrogenasa/genética , Ratones , Mutación/genéticaRESUMEN
Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.
Asunto(s)
Adenosina/análogos & derivados , Antígenos de Neoplasias/metabolismo , Eliminación de Gen , Metionina Adenosiltransferasa/metabolismo , Neoplasias/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Purina-Nucleósido Fosforilasa/metabolismo , Transducción de Señal , Tionucleósidos/metabolismo , Adenosina/metabolismo , Genómica , Células HCT116 , Humanos , Complejos Multiproteicos/metabolismo , Neoplasias/metabolismo , Purina-Nucleósido Fosforilasa/deficiencia , ARN Interferente Pequeño/metabolismoRESUMEN
Mutations of IDH1 and IDH2, which produce the oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors, including acute myeloid leukemia. Recent studies have shown that expression of the IDH mutant enzymes results in high levels of 2HG and a block in cellular differentiation that can be reversed with IDH mutant-specific small-molecule inhibitors. To further understand the role of IDH mutations in cancer, we conducted mechanistic studies in the TF-1 IDH2 R140Q erythroleukemia model system and found that IDH2 mutant expression caused both histone and genomic DNA methylation changes that can be reversed when IDH2 mutant activity is inhibited. Specifically, histone hypermethylation is rapidly reversed within days, whereas reversal of DNA hypermethylation proceeds in a progressive manner over the course of weeks. We identified several gene signatures implicated in tumorigenesis of leukemia and lymphoma, indicating a selective modulation of relevant cancer genes by IDH mutations. As methylation of DNA and histones is closely linked to mRNA expression and differentiation, these results indicate that IDH2 mutant inhibition may function as a cancer therapy via histone and DNA demethylation at genes involved in differentiation and tumorigenesis.
Asunto(s)
Metilación de ADN/genética , Inhibidores Enzimáticos/farmacología , Histonas/genética , Isocitrato Deshidrogenasa/genética , Mutación , Transcriptoma/efectos de los fármacos , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cromatografía Liquida , Histonas/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Compuestos de Fenilurea/farmacología , Análisis de Componente Principal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfonamidas/farmacología , Espectrometría de Masas en TándemRESUMEN
Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
Asunto(s)
Neoplasias de los Conductos Biliares/patología , Diferenciación Celular/genética , Colangiocarcinoma/patología , Factor Nuclear 4 del Hepatocito/antagonistas & inhibidores , Hepatocitos/patología , Isocitrato Deshidrogenasa/genética , Proteínas Mutantes/metabolismo , Animales , Neoplasias de los Conductos Biliares/enzimología , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/enzimología , Conductos Biliares Intrahepáticos/patología , División Celular/genética , Linaje de la Célula/genética , Colangiocarcinoma/enzimología , Colangiocarcinoma/genética , Modelos Animales de Enfermedad , Femenino , Glutaratos/metabolismo , Factor Nuclear 4 del Hepatocito/biosíntesis , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteínas Mutantes/genética , Mutación/genética , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Células Madre/patología , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hematopoyesis/efectos de los fármacos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/enzimología , Compuestos de Fenilurea/farmacología , Sulfonamidas/farmacología , Sitio Alostérico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular , Células Cultivadas , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Eritropoyesis/efectos de los fármacos , Regulación Leucémica de la Expresión Génica , Glutaratos/metabolismo , Humanos , Isocitrato Deshidrogenasa/química , Isocitrato Deshidrogenasa/metabolismo , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Terapia Molecular Dirigida , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Mutación Puntual , Multimerización de Proteína , Estructura Secundaria de Proteína , Bibliotecas de Moléculas Pequeñas , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Asunto(s)
Amidas/química , Complemento C1s/antagonistas & inhibidores , Diseño de Fármacos , Polietilenglicoles/química , Inhibidores de Proteasas/síntesis química , Tiofenos/química , Animales , Complemento C1s/metabolismo , Semivida , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Dioxigenasas/metabolismo , Glutaratos/química , Glutaratos/farmacología , Proteínas Nucleares/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Dioxigenasas/genética , Activación Enzimática/efectos de los fármacos , Glioma/enzimología , Glioma/genética , Glioma/metabolismo , Glioma/patología , Glutaratos/metabolismo , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Proteínas Nucleares/genética , Oncogenes , Procolágeno-Prolina Dioxigenasa/genéticaRESUMEN
Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and â¼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.
RESUMEN
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Quinolinas/química , Sulfonas/química , Animales , Aterosclerosis/tratamiento farmacológico , Sitios de Unión , Línea Celular , Simulación por Computador , Humanos , Lipoproteínas LDL/deficiencia , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Receptores X del Hígado , Ratones , Ratones Noqueados , Microsomas/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/uso terapéuticoRESUMEN
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Sitios de Unión , Línea Celular , Simulación por Computador , Humanos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Enlace de Hidrógeno , Receptores X del Hígado , Ratones , Microsomas Hepáticos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRbeta binding IC(50) values <10nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.
Asunto(s)
Bencimidazoles/síntesis química , Receptores Nucleares Huérfanos/agonistas , Sulfonas/química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Línea Celular , Humanos , Receptores X del Hígado , Ratones , Microsomas Hepáticos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , ARN Mensajero/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Asunto(s)
Complemento C1s/antagonistas & inhibidores , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Animales , Sitios de Unión , Semivida , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.