RESUMEN
Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).
Asunto(s)
Dermatitis Atópica/genética , Interleucina-13/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Humanos , Transducción de SeñalRESUMEN
GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bioavailable small-molecule inhibitor of checkpoint kinase 1 that was investigated as a novel cotherapy to potentiate chemotherapeutic drugs, such as gemcitabine. In a radiolabeled absorption, distribution, metabolism, and excretion study in Sprague-Dawley rats, trace-level but long-lived 14C-labeled thiocyanate was observed in circulation. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation. Cytochrome P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes, and in the presence of 18O2, one atom of 18O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121-154 µM in rats and 71-110 µM in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of <1% of the administered GDC-0425 and contributed less than 1 µM thiocyanate to systemic levels. Further, in vitro studies showed only trace oxidative decyanation for humans. These data indicated that, although cyanide was metabolically released from GDC-0425 and formed low levels of thiocyanate, this pathway was a minor route of metabolism, and GDC-0425-related increases in systemic thiocyanate were unlikely to pose safety concerns for subjects of clinical studies.
Asunto(s)
Antineoplásicos/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piperidinas/farmacocinética , Tiocianatos/metabolismo , Administración Oral , Animales , Antineoplásicos/sangre , Antineoplásicos/orina , Biotransformación , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Femenino , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/orina , Masculino , Tasa de Depuración Metabólica , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piperidinas/sangre , Piperidinas/orina , Ratas Sprague-Dawley , Tiocianatos/sangre , Distribución TisularRESUMEN
Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.
Asunto(s)
Relojes Biológicos/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Dextroanfetamina/farmacología , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Haloperidol/farmacología , Memoria/efectos de los fármacos , Animales , Condicionamiento Operante/efectos de los fármacos , Masculino , Mesocricetus , Percepción del Tiempo/efectos de los fármacosRESUMEN
Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism. Our studies show that extracellular phosphate uptake through solute carrier family 20 (phosphate transporter), member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SLC20a1 abrogates osteogenic differentiation by decreasing intramitochondrial phosphate and ATP synthesis. Collectively, this study offers the demonstration of a previously unknown mechanism for the beneficial role of CaP biomaterials in bone repair and the role of phosphate ions in bone physiology and regeneration. These findings also begin to shed light on the role of ATP metabolism in bone homeostasis, which may be exploited to treat bone metabolic diseases.
Asunto(s)
Adenosina/metabolismo , Fosfatos de Calcio/química , Regulación de la Expresión Génica , Células Madre/citología , Adenosina Trifosfato/metabolismo , Materiales Biocompatibles/química , Huesos/metabolismo , Fosfatos de Calcio/metabolismo , Diferenciación Celular , Células Cultivadas/citología , Cromatografía Líquida de Alta Presión , Homeostasis , Humanos , Células Madre Mesenquimatosas/citología , Osteogénesis/fisiología , Fenotipo , Fosfatos/metabolismo , ARN Interferente Pequeño/metabolismo , Receptor de Adenosina A2B/metabolismo , Regeneración , Transducción de Señal , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismoRESUMEN
(R)-2-Amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one (GNE-892) is an orally administered inhibitor of ß-secretase 1 (ß-site amyloid precursor protein cleaving enzyme 1, BACE1) that was developed as an intervention therapy against Alzheimer's disease. A clinical microdosing strategy was being considered for de-risking the potential pharmacokinetic liabilities of GNE-892. We tested whether dose-proportionality was observed in cynomolgus monkey as proof-of-concept for a human microdosing study. With cryopreserved monkey hepatocytes, concentration-dependency for substrate turnover and the relative contribution of P450- versus AO-mediated metabolism were observed. Characterization of the kinetics of these metabolic pathways demonstrated differences in the affinities of P450 and AO for GNE-892, which supported the metabolic profiles that had been obtained. To test if this metabolic shift occurred in vivo, mass balance studies in monkeys were conducted at doses of 0.085 and 15 mg/kg. Plasma exposure of GNE-892 following oral administration was more than 20-fold greater than dose proportional at the high-dose. P-gp-mediated efflux was unable to explain the discrepancy. The profiles of metabolites in circulation and excreta were indicative that oxidative metabolism limited the exposure to unchanged GNE-892 at the low dose. Further, the in vivo data supported the concentration-dependent metabolic shift between P450 and AO. In conclusion, microdosing of GNE-892 was not predictive of pharmacokinetics at a more pharmacologically relevant dose due to saturable absorption and metabolism. Therefore, it is important to consider ADME liabilities and their potential concentration-dependency when deciding upon a clinical microdosing strategy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Aldehído Oxidasa/fisiología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sistema Enzimático del Citocromo P-450/fisiología , Inhibidores Enzimáticos/metabolismo , Imidazoles/metabolismo , Compuestos de Espiro/metabolismo , Animales , Macaca fascicularis , MasculinoRESUMEN
Application of safety lead optimization screening strategies during the early stage of drug discovery led to the identification of a series of CNS-active small molecule inhibitors with opioid off-target effects, as evidenced by potent agonistic activity in functional cell-based assays for mu (MOP), kappa (KOP) and delta (DOP) opioid receptors. The translation of these effects was confirmed in vivo with the following observations: hypoactivity and decreased fecal production in rats (characteristic of MOP agonism); increased urine production in rats (characteristic of KOP agonism); and decreased intestinal transit time in mice, which was partially blocked by the MOP antagonist naloxone, demonstrating that the in vivo effects were specific for MOP. Based on the confirmation of in vitro-in vivo translatability, an in vitro screening strategy was implemented that resulted in the identification of an optimized backup molecule, devoid of in vivo off-target opioid effects. In addition, in silico modeling by docking of the various molecules to the opioid receptors allowed the identification of the structural drivers of these off-target effects, which can be applied to future chemical-design criteria. Thus, implementation of the safety lead optimization strategy described in this article demonstrates the utility and impact of such approaches on risk mitigation and identification of lead small molecules with improved safety profiles.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteasas/farmacología , Receptores Opioides/agonistas , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Células CHO , Cricetulus , Defecación/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Tránsito Gastrointestinal/efectos de los fármacos , Cobayas , Íleon/efectos de los fármacos , Íleon/metabolismo , Técnicas In Vitro , Ratones , Simulación del Acoplamiento Molecular , Antagonistas de Narcóticos/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/toxicidad , Unión Proteica , Conformación Proteica , Ratas Sprague-Dawley , Receptores Opioides/genética , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Factores de Tiempo , Transfección , Micción/efectos de los fármacosRESUMEN
We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a ß-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/metabolismo , Imidazoles/metabolismo , Pirazoles/metabolismo , Pirimidinas/metabolismo , Compuestos de Espiro/metabolismo , Animales , Bilis/metabolismo , Biotransformación , Células Cultivadas , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/orina , Heces/química , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Imidazoles/farmacocinética , Imidazoles/orina , Masculino , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/orina , Espectrometría de Masas en TándemRESUMEN
The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Aß in wild type rats after a single dose.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Benzopiranos/farmacología , Oxazoles/farmacología , Inhibidores de Proteasas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Benzopiranos/síntesis química , Benzopiranos/química , Relación Dosis-Respuesta a Droga , Humanos , Microsomas Hepáticos/enzimología , Conformación Molecular , Oxazoles/síntesis química , Oxazoles/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Ratas , Relación Estructura-Actividad , PorcinosRESUMEN
This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of ß-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), GNE-629 [(4S,4a'S,10a'S)-2-amino-8'-(2-fluoropyridin-3-yl)-1-methyl-3',4',4a',10a'-tetrahydro-1'H-spiro[imidazole-4,10'-pyrano[4,3-b]chromen]-5(1H)-one] and GNE-892 [(R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one], and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid ß (Aß) in the plasma and cerebrospinal fluid (CSF), and secreted APPß (sAPPß) and secreted APPα (sAPPα) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Aß and CSF Aß, sAPPα, and sAPPß using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC50 of 0.0033 µM and 0.065 µM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Aß formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Aß, sAPPß, and sAPPα in the CSF, and Aß in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Compuestos de Espiro/farmacología , Secuencia de Aminoácidos , Animales , Cromatografía Liquida , Perros , Células HEK293 , Humanos , Macaca fascicularis , Modelos Biológicos , Datos de Secuencia Molecular , Pirimidinas/farmacología , Espectrometría de Masas en Tándem , Tiazinas/farmacologíaRESUMEN
The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.
Asunto(s)
Amitrol (Herbicida)/química , Amitrol (Herbicida)/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Triazoles/química , Triazoles/uso terapéutico , Amitrol (Herbicida)/farmacología , Animales , Antineoplásicos/farmacología , Cristalografía por Rayos X , Humanos , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/farmacocinética , Sulfonamidas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacología , Glutatión/farmacocinética , Células HEK293 , Humanos , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.
Asunto(s)
Antineoplásicos , Fosfatidilinositol 3-Quinasas Clase III , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Autofagia , Endosomas , Fosfatidilinositol 3-Quinasa/metabolismo , FosforilaciónRESUMEN
Starting from thienobenzopyran HTS hit 1, co-crystallization, molecular modeling and metabolic analysis were used to design potent and metabolically stable inhibitors of PI3-kinase. Compound 15 demonstrated PI3K pathway suppression in a mouse MCF7 xenograft model.
Asunto(s)
Benzoxepinas/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Tiofenos/síntesis química , Animales , Benzoxepinas/química , Benzoxepinas/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.
Asunto(s)
Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinonas/uso terapéutico , Quinasas raf/antagonistas & inhibidores , Animales , Azetidinas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Células de Riñón Canino Madin Darby , Ratones Desnudos , Estructura Molecular , Mutación , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Piperidinas/uso terapéutico , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Quinazolinonas/química , Quinazolinonas/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/genética , Quinasas raf/metabolismoRESUMEN
Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date.
RESUMEN
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Sulfonamidas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animales , Línea Celular , Simulación por Computador , Cricetinae , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
The development of bacterial endocarditis as a result of endoscopic interventions within the gastrointestinal tract is exceedingly rare. Antibiotic prophylaxis for endoscopic procedures is generally not warranted, except for certain high-risk patients. Double-balloon enteroscopy (DBE) is a common endoscopic procedure for evaluation of the small bowel. Bacterial endocarditis secondary to DBE has not been previously described. We describe the first case of enterococcal endocarditis attributed to DBE in a patient with a history of stage 1 primary biliary cholangitis.
RESUMEN
The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells.
Asunto(s)
Diseño de Fármacos , Inmunidad Celular/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/síntesis química , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Inmunidad Celular/fisiología , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Estructura Terciaria de ProteínaRESUMEN
Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small molecules that have been utilized to inhibit DLK kinase activity in vivo. These compounds represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.
Asunto(s)
Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Enfermedades Neurodegenerativas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Proteínas de Unión al Calcio , Humanos , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Ranitidine is a widely used over-the-counter antacid medication, and is generally very well tolerated. To our knowledge, anaphylaxis secondary to ranitidine is exceedingly rare, and has only been reported in a few case reports. We present a patient who developed an anaphylactic reaction after one tablespoon of ranitidine. The goal of this manuscript is to add to the paucity of literature of this rare but life-threatening adverse effect of a commonly used medication.