RESUMO
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.
Assuntos
Cisteína , Neoplasias , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Cisteína/metabolismo , Cisteína/química , Ligantes , Melanoma/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , NF-kappa B/química , NF-kappa B/metabolismo , Oxirredução , Transdução de Sinais , Fatores de Transcrição SOXE/química , Fatores de Transcrição SOXE/metabolismoRESUMO
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.
Assuntos
Caproatos/farmacologia , Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Caproatos/química , Caproatos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Xantenos/química , Xantenos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Linhagem Celular , Células HEK293 , Humanos , Inibidores de Proteases/síntese química , Ratos , Xantenos/síntese químicaRESUMO
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.
RESUMO
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.
Assuntos
Etnicidade , Assistentes Médicos , Humanos , Masculino , Feminino , Estados Unidos , Âmbito da Prática , Grupos Minoritários , Salários e BenefíciosRESUMO
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.
Assuntos
Peso Corporal/fisiologia , Proteínas de Homeodomínio/fisiologia , Homeostase/fisiologia , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Composição Corporal/efeitos dos fármacos , Composição Corporal/genética , Composição Corporal/fisiologia , Dieta , Eletrofisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Homeostase/efeitos dos fármacos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/fisiopatologia , Técnicas de Patch-Clamp , Fenótipo , Sondas RNA , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores para Leptina , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator Esteroidogênico 1 , Fatores de Transcrição/genética , Núcleo Hipotalâmico Ventromedial/citologiaRESUMO
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.
RESUMO
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.
Assuntos
Receptor CB2 de Canabinoide/agonistas , Sulfonas/química , Amidas/química , Amidas/farmacologia , Animais , Humanos , Microssomos Hepáticos , Farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
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.
Assuntos
Dieta , Obesidade/genética , Hormônios Peptídicos/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologia , Tecido Adiposo/metabolismo , Alelos , Análise de Variância , Ração Animal , Animais , Glicemia/metabolismo , Southern Blotting , Western Blotting , Composição Corporal , Peso Corporal , Cruzamentos Genéticos , DNA/metabolismo , Feminino , Deleção de Genes , Predisposição Genética para Doença , Genótipo , Grelina , Heterozigoto , Homeostase , Hiperglicemia/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Neurônios/metabolismo , Obesidade/metabolismo , Hormônios Peptídicos/química , Fenótipo , RNA Mensageiro/metabolismo , Receptores de Grelina , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Recombinação Genética , Transdução de Sinais , Coloração pela Prata , Fatores de TempoRESUMO
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.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridonas/síntese química , Quinazolinas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Naftalenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neovascularização da Córnea/sangue , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Microssomos Hepáticos/metabolismo , Oxidiazóis , Receptor CB2 de Canabinoide/agonistas , Animais , Técnicas de Química Combinatória , Humanos , Conformação Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Aminopiridinas/síntese química , Anti-Inflamatórios/síntese química , Carbamatos/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Pirimidinas/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Células Jurkat , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Benzamidas/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Quinazolinas/síntese química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Técnicas In Vitro , Interleucina-2/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Amiodarona/uso terapêutico , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Tromboembolia/tratamento farmacológico , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fumar , Tromboembolia/sangue , Tromboembolia/complicações , Tromboembolia/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/metabolismo , Insulina/farmacologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Espectrometria de Massas , Camundongos , Dados de Sequência Molecular , Mutação , Placa Amiloide/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Recombinantes , Especificidade por SubstratoRESUMO
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.
RESUMO
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.