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Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.
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Cisteína , Neoplasias , Animales , Humanos , Ratones , Línea Celular Tumoral , Cisteína/metabolismo , Cisteína/química , Ligandos , Melanoma/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , FN-kappa B/química , FN-kappa B/metabolismo , Oxidación-Reducción , Transducción de Señal , Factores de Transcripción SOXE/química , Factores de Transcripción SOXE/metabolismoRESUMEN
The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.
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Caproatos/farmacología , Descubrimiento de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Caproatos/química , Caproatos/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Relación Estructura-ActividadRESUMEN
The ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aß levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Xantenos/química , Xantenos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Línea Celular , Células HEK293 , Humanos , Inhibidores de Proteasas/síntesis química , Ratas , Xantenos/síntesis químicaRESUMEN
INTRODUCTION: Inadequate clinical training site availability may inhibit physician assistant/associate (PA), advanced practice nursing (APN), and physician workforce growth. Educational institutions increasingly incentivize clinical training sites with financial compensation, with potential implications for educational costs and enrollment. This study investigated compensation trends among PA programs. METHODS: Data from the 2013 to 2019 PA Education Association Program Reports were examined. Multivariate logistic and linear regressions were estimated to identify the influence of PA program characteristics on clinical training site compensation. The effect of compensation on program enrollment was determined with a difference-in-differences estimator. RESULTS: Physician assistant/associate programs collectively paid nearly $19 million to clinical training sites in 2019. The percentage of programs that offer financial incentives increased from 22.2% in 2013 to 52.3% in 2019. Over this time, public institutions affiliated with academic health centers (AHCs) were least likely to offer compensation. Higher compensation rates were observed in Census divisions with greater number of programs, and programs located in New England were the most likely to offer compensation. Offering compensation did not influence growth in programs' enrollment. DISCUSSION: Compensation trends highlight increasing demand for PA clinical training sites, especially in areas with greater regional competition. Compensation is primarily driven by private institutions unaffiliated with AHCs. Programs likely offer compensation to maintain, rather than grow, enrollment. Additional investigation should incorporate medical school and APN program data to more fully examine the impact of these costs on learners, institutions, and the health care workforce.
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High labor demand for physician assistants/associates (PA) has led to substantial PA workforce and wage growth. During this growth period, states have adopted reforms to reduce PA scope of practice restrictions and reports of significant gender and race wage disparities have emerged. This study examined data from the American Community Survey to investigate the influence of demographic characteristics, human capital, and scope of practice reforms on PA wages from 2008 to 2017. Using an ordinary least squares two-way fixed effects estimator, a significant association between reforms and PA wages could not be established. Rather, wages were found to be strongly associated with human capital and demographic characteristics. Gender and race wage disparities persist, with female PAs earning 7.5% lower wages than male PAs and White PAs earning 9.1% to 14.5% higher wages than racial and ethnic minority PAs. These findings suggest a minimal influence of prior scope of practice reforms on PA wages.
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Etnicidad , Asistentes Médicos , Humanos , Masculino , Femenino , Estados Unidos , Alcance de la Práctica , Grupos Minoritarios , Salarios y BeneficiosRESUMEN
Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.
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Peso Corporal/fisiología , Proteínas de Homeodominio/fisiología , Homeostasis/fisiología , Leptina/farmacología , Neuronas/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , Núcleo Hipotalámico Ventromedial/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/fisiología , Animales , Composición Corporal/efectos de los fármacos , Composición Corporal/genética , Composición Corporal/fisiología , Dieta , Electrofisiología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Proteínas Fluorescentes Verdes/metabolismo , Proteínas de Homeodominio/genética , Homeostasis/efectos de los fármacos , Inmunohistoquímica , Técnicas In Vitro , Masculino , Ratones , Ratones Transgénicos , Obesidad/fisiopatología , Técnicas de Placa-Clamp , Fenotipo , Sondas ARN , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Leptina , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor Esteroidogénico 1 , Factores de Transcripción/genética , Núcleo Hipotalámico Ventromedial/citologíaRESUMEN
The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.
RESUMEN
A series of alpha-amidosulfones were found to be potent and selective agonists of CB(2). The discovery, synthesis, and structure-activity relationships of this series of agonists are reported. In addition, the pharmacokinetic properties of the most promising compounds are profiled.
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Receptor Cannabinoide CB2/agonistas , Sulfonas/química , Amidas/química , Amidas/farmacología , Animales , Humanos , Microsomas Hepáticos , Farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonas/farmacologíaRESUMEN
Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.
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Dieta , Obesidad/genética , Hormonas Peptídicas/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Tejido Adiposo/metabolismo , Alelos , Análisis de Varianza , Alimentación Animal , Animales , Glucemia/metabolismo , Southern Blotting , Western Blotting , Composición Corporal , Peso Corporal , Cruzamientos Genéticos , ADN/metabolismo , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Genotipo , Ghrelina , Heterocigoto , Homeostasis , Hiperglucemia/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Genéticos , Neuronas/metabolismo , Obesidad/metabolismo , Hormonas Peptídicas/química , Fenotipo , ARN Mensajero/metabolismo , Receptores de Ghrelina , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Recombinación Genética , Transducción de Señal , Tinción con Nitrato de Plata , Factores de TiempoRESUMEN
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
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Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-kit/metabolismo , Piridonas/síntesis química , Quinazolinas/síntesis química , Administración Oral , Animales , Cristalografía por Rayos X , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacocinética , Piridonas/farmacología , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
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Antineoplásicos/farmacología , Células Endoteliales/efectos de los fármacos , Naftalenos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neovascularización de la Córnea/sangre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structural modifications to the central portion of the N-arylamide oxadiazole scaffold led to the identification of N-arylpiperidine oxadiazoles as conformationally constrained analogs that offered improved stability and comparable potency and selectivity. The simple, modular scaffold allowed for the use of expeditious and divergent synthetic routes, which provided two-directional SAR in parallel. Several potent and selective agonists from this novel ligand class are described.
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Microsomas Hepáticos/metabolismo , Oxadiazoles , Receptor Cannabinoide CB2/agonistas , Animales , Técnicas Químicas Combinatorias , Humanos , Conformación Molecular , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The detection of atrial fibrillation (AF) is important for stroke prevention in patients with AF. This paper aimed to investigate the current landscape of smartphone-based arrhythmia detection and monitoring. The current technology can be divided into smartphone-based photoplethysmography (PPG) and smartphone-based single-lead electrocardiograms (ECGs). Our literature review concluded there are currently no validated PPG applications for the detection of arrhythmias available to the general population. However, an initial validation study indicates that the current development in Cardiio Rhythm PPG application, when made available, could provide an accurate and reliable means to detect AF in patients at risk of developing AF. The smartphone-based single-lead ECG devices are more promising. Multiple studies have shown the AliveCor smartphone ECG to be a reliable and accurate means of detecting atrial fibrillation. A drawback is that this device strictly provides data and is not capable of making a diagnosis of atrial fibrillation. The recorded ECG needs to be sent to a physician or medical professional for further review. In conclusion, these devices show promise in arrhythmia assessment, managing patients with AF, and diagnosing AF early in high risk patients. Caution should be used when assessing data provided by these devices, as validation in a real-world setting is still underway.
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As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer's disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study.
RESUMEN
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
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Aminopiridinas/síntesis química , Antiinflamatorios/síntesis química , Carbamatos/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Pirimidinas/síntesis química , Administración Oral , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Disponibilidad Biológica , Carbamatos/química , Carbamatos/farmacología , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Células Jurkat , Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
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Antiinflamatorios no Esteroideos/síntesis química , Benzamidas/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Quinazolinas/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Técnicas In Vitro , Interleucina-2/biosíntesis , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Clinical trials have reported a low time in therapeutic range (TTR) in patients with atrial fibrillation treated with both warfarin andamiodarone. These trials included centers and countries with both high and low TTRs. What is the impact of amiodarone on the TTR in a single, high-quality anticoagulation clinic? TTR was assessed in amiodarone and nonamiodarone-treated patients from a University anticoagulation clinic. Baseline characteristics between patients ever-taking or never-taking amiodarone were similar, except more amiodarone patients were smokers (19.5 vs. 6.1%, Pâ=â0.0031). The TTR calculated from 8901international normalized ratios (INRs) in 249 nonamiodarone patients with a mean follow-up of 34â±â20 months (mean INR 36â±â18) was 66â±â16.6% compared with 61.3â±â16.2% (Pâ=â0.111) from 1455 INRs in 41 amiodarone-treated patients with a mean follow-up of 28â±â20 months (mean INR 35â±â22). Factors associated with a low TTR were male sex (Pâ=â0.0013), smoker (Pâ=â0.0048), and amiodarone use (Pâ=â0.0374). A second on-treatment analysis, in which the TTR was calculated only during amiodarone therapy, resulted in similar findings; however, amiodarone did not emerge as a predictor of a low TTR. In 11 patients, the TTR prior to amiodarone (54.5â±â22.2%) was not significantly different in the first 3 months (54.6â±â33.4%) or after 3 months (67.2â±â33.7%) of amiodarone. In a single high-quality anticoagulation center, anticoagulation quality, as measured by the TTR, can be comparable in amiodarone and nonamiodarone-treated patients.
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Amiodarona/uso terapéutico , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Tromboembolia/tratamiento farmacológico , Warfarina/uso terapéutico , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Fibrilación Atrial/patología , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Factores Sexuales , Fumar , Tromboembolia/sangre , Tromboembolia/complicaciones , Tromboembolia/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer's disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Línea Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Humanos , Insulina/metabolismo , Insulina/farmacología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Espectrometría de Masas , Ratones , Datos de Secuencia Molecular , Mutación , Placa Amiloide/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Recombinantes , Especificidad por SustratoRESUMEN
BACE1 inhibition to prevent Aß peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aß levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.
RESUMEN
The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated from Acanthella sp., is reported. The decalin framework was established via an intramolecular Diels-Alder cycloaddition and subsequently functionalized through a series of substrate-controlled diastereoselective transformations to install the tertiary isonitrile, beta-hydroxy isonitrile, and pendant tetrahydrofuranyl ring.