RESUMEN
We describe the synthesis of a series of 3-t-butyl 5-aminopyrazole p-substituted arylamides as inhibitors of serine-threonine25 (STK25), an enzyme implicated in the progression of non-alcoholic fatty liver disease (NAFLD). Appending a p-N-pyrrolidinosulphonamide group to the arylamide group led to a 'first-in kind' inhibitor with IC50 = 228 nM. A co-crystal structure with STK 25 revealed productive interactions which were also reproduced using molecular docking. A new series of triazolo dihydro oxazine carboxamides of 3-t-butyl 5-aminopyrazole was not active against STK25.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Péptidos y Proteínas de Señalización Intracelular , Simulación del Acoplamiento Molecular , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Oxazinas , Proteínas Serina-Treonina Quinasas , Serina , Treonina , Rayos XRESUMEN
Multi-parameter optimization (MPO) is a major challenge in new chemical entity (NCE) drug discovery. Recently, promising results were reported for deep learning generative models applied to de novo molecular design, but, to our knowledge, until now no report was made of the value of this new technology for addressing MPO in an actual drug discovery project. In this study, we demonstrate the benefit of applying AI technology in a real drug discovery project. We evaluate the potential of a ligand-based de novo design technology using deep learning generative models to accelerate the obtention of lead compounds meeting 11 different biological activity objectives simultaneously. Using the initial dataset of the project, we built QSAR models for all the 11 objectives, with moderate to high performance (precision between 0.67 and 1.0 on an independent test set). Our DL-based AI de novo design algorithm, combined with the QSAR models, generated 150 virtual compounds predicted as active on all objectives. Eleven were synthetized and tested. The AI-designed compounds met 9.5 objectives on average (i.e., 86% success rate) versus 6.4 (i.e., 58% success rate) for the initial molecules measured on all objectives. One of the AI-designed molecules was active on all 11 measured objectives, and two were active on 10 objectives while being in the error margin of the assay for the last one. The AI algorithm designed compounds with functional groups, which, although being rare or absent in the initial dataset, turned out to be highly beneficial for the MPO.
Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Algoritmos , Descubrimiento de Drogas/métodos , LigandosRESUMEN
Carnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested a pivotal role of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity and mitochondrial homeostasis. Thus, we tested the potential of GSK773, a novel direct AMPK activator, to improve or correct FAO capacities in muscle cells from patients harboring various mutations. We used controls' and patients' myotubes and studied the parameters of FAO metabolism, of mitochondrial quantity and quality and of differentiation. We found that AMPK is constitutively activated in patients' myotubes, which exhibit both reduced FAO and impaired differentiation. GSK773 improves or corrects several metabolic hallmarks of CPT2 deficiency (deficient FAO flux and C16-acylcarnitine accumulation) by upregulating the expression of CPT2 protein. Beneficial effects of GSK773 are also likely due to stimulation of mitochondrial biogenesis and induction of mitochondrial fusion, by decreasing dynamin-related protein 1 and increasing mitofusin 2. GSK773 also induces a shift in myosin heavy chain isoforms toward the slow oxidative type and, therefore, fully corrects the differentiation process. We establish, through small interfering RNA knockdowns and pharmacological approaches, that these GSK773 effects are mediated through peroxisome proliferator-activated receptor gamma co-activator 1-alpha, reactive oxygen species and p38 mitogen-activated protein kinase, all key players of skeletal muscle plasticity. GSK773 recapitulates several important features of skeletal muscle adaptation to exercise. The results show that AMPK activation by GSK773 evokes the slow, oxidative myogenic program and triggers beneficial phenotypic adaptations in FAO-deficient myotubes. Thus, GSK773 might have therapeutic potential for correction of CPT2 deficiency.
Asunto(s)
Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/genética , Metabolismo de los Lípidos/genética , Errores Innatos del Metabolismo/genética , Proteínas Quinasas/genética , Quinolonas/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Carnitina O-Palmitoiltransferasa/efectos de los fármacos , Ácidos Grasos/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Errores Innatos del Metabolismo/fisiopatología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Cadenas Pesadas de Miosina/genética , PPAR alfa/genética , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.
Asunto(s)
Diseño de Fármacos , Piperazina/química , Piperidinas/química , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Cristalografía por Rayos X , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Canal de Potasio ERG1/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Piperazina/síntesis química , Piperazina/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Animales , Inhibidores Enzimáticos/uso terapéutico , Humanos , RatasRESUMEN
A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Pancreatitis/tratamiento farmacológico , Animales , Benzoxazoles/química , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Indazoles/química , Indazoles/farmacocinética , Indazoles/farmacología , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Pancreatitis/enzimología , Pancreatitis/metabolismo , Ratas , Triptófano/metabolismoRESUMEN
Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.
Asunto(s)
Benzoxazoles/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Insuficiencia Multiorgánica/genética , Oxazolidinonas/farmacología , Pancreatitis/genética , Propionatos/farmacología , ARN Mensajero/metabolismo , Enfermedad Aguda , Animales , Cromatografía Liquida , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Células HEK293 , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Riñón/metabolismo , Riñón/patología , Quinurenina 3-Monooxigenasa/genética , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Noqueados , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/patología , Páncreas/metabolismo , Páncreas/patología , Pancreatitis/complicaciones , Pancreatitis/patología , Ratas , Espectrometría de Masas en Tándem , Triptófano/metabolismoRESUMEN
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
Asunto(s)
Aminoquinolinas/síntesis química , Antiinflamatorios/síntesis química , Apolipoproteína A-I/metabolismo , Benzoatos/síntesis química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/síntesis química , Factores de Transcripción/antagonistas & inhibidores , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Proteínas de Ciclo Celular , Descubrimiento de Drogas , Humanos , Ratones , Quinolinas/farmacocinética , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Proteínas Cromosómicas no Histona , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Histonas/química , Histonas/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Naftiridinas/química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
Asunto(s)
Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Apolipoproteína A-I/biosíntesis , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacocinética , Proteínas de Ciclo Celular , Perros , Epigénesis Genética , Humanos , Macaca fascicularis , Ratones , Modelos Moleculares , Permeabilidad , Estructura Terciaria de Proteína , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose.
RESUMEN
Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD). In I/R, neither compound reduced infarct size 24 h after reperfusion. In SHR-SP, HSFD increased MAP, urine output, microalbuminuria, and mortality, caused left ventricular hypertrophy with preserved ejection fraction, and impaired endothelium-dependent vasorelaxation. The low dose of BAY 60-4552, but not that of GSK2181236A, decreased urine output, and improved survival. Conversely, the low dose of GSK2181236A, but not that of BAY 60-4552, attenuated the development of cardiac hypertrophy. The high doses of both compounds similarly attenuated cardiac hypertrophy and improved survival. In addition to these effects, the high dose of BAY 60-4552 reduced urine output and microalbuminuria and attenuated the increase in MAP to a greater extent than did GSK2181236A. Neither compound improved endothelium-dependent vasorelaxation. In SHR-SP isolated aorta, the vasodilatory responses to the NO-dependent compounds carbachol and sodium nitroprusside were attenuated by HSFD. In contrast, the vasodilatory responses to both GSK2181236A and BAY 60-4552 were unaltered by HSFD, indicating that reduced NO-bioavailability and not changes in the oxidative state of sGC is responsible for the vascular dysfunction. In summary, GSK2181236A and BAY 60-4552 provide partial benefit against hypertension-induced end-organ damage. The differential beneficial effects observed between these compounds could reflect tissue-specific changes in the oxidative state of sGC and might help direct the clinical development of these novel classes of therapeutic agents.
RESUMEN
The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.
Asunto(s)
Apolipoproteína A-I/metabolismo , Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Quinolinas/química , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Células Hep G2 , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso , Proteínas Nucleares/metabolismo , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/química , Isoxazoles/síntesis química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Quinolinas/síntesis química , Animales , Sitios de Unión , Cristalografía por Rayos X , Cobayas , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Inflamación/tratamiento farmacológico , Isoxazoles/química , Isoxazoles/farmacología , Ratones , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , RatasRESUMEN
Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.
Asunto(s)
Toxinas Bacterianas/síntesis química , Úlcera de Buruli/inducido químicamente , Macrólidos/síntesis química , Animales , Toxinas Bacterianas/química , Toxinas Bacterianas/farmacología , Úlcera de Buruli/microbiología , Úlcera de Buruli/patología , Fibroblastos/efectos de los fármacos , Macrólidos/química , Macrólidos/farmacología , Ratones , Estructura Molecular , Infecciones por Mycobacterium/patología , Mycobacterium ulcerans/química , Relación Estructura-ActividadRESUMEN
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Asunto(s)
Cromatina/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Cromatina/genética , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Modelos Moleculares , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Unión Proteica/efectos de los fármacos , Proteómica , Transcripción Genética/efectos de los fármacosRESUMEN
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.
Asunto(s)
Apolipoproteína A-I/genética , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Acetilación , Secuencia de Aminoácidos , Apolipoproteína A-I/química , Apolipoproteína A-I/metabolismo , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Sitios de Unión , Cristalografía por Rayos X , Descubrimiento de Drogas , Epigenómica , Células Hep G2 , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Lisina/química , Lisina/genética , Lisina/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Terapia Molecular Dirigida , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Estereoisomerismo , Factores de Transcripción , Regulación hacia ArribaRESUMEN
Hydrazinocyclohexadienes, easily prepared by an ene-reaction between commercially available azodicarboxylate reagents and cyclohexadiene, are interesting substrates for desymmetrization reactions. Under Sharpless asymmetric dihydroxylation conditions, they can lead efficiently to several chiral building blocks as well as advanced precursors of biologically active compounds.
Asunto(s)
Ciclohexanos/síntesis química , Ciclohexenos/química , Hidrazinas/química , Catálisis , Ciclohexanos/química , Estructura MolecularRESUMEN
Beta-amino alcohols derived from natural amino acids have been used extensively as a powerful source of chirality. Transformation of the hydroxy group of these beta-amino alcohols into a good leaving group, by using trifluoroacetic anhydride, led to rearranged beta-amino alcohols in good yields and with high enantiomeric excesses. This rearrangement has allowed the transformation of substituted prolinols to substituted 3-hydroxypiperidines and linear beta-amino alcohols, issued from natural amino acids, to rearranged beta-amino alcohols.