RESUMO
Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Animais , Peptídeos beta-Amiloides/metabolismo , Ratos , Relação Estrutura-Atividade , Camundongos , Masculino , Descoberta de Drogas , Furanos/farmacologia , Furanos/farmacocinética , Furanos/síntese química , Furanos/química , Furanos/uso terapêutico , Ratos Sprague-Dawley , Encéfalo/metabolismoRESUMO
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Encéfalo , Esclerose Múltipla , Inibidores de Proteínas Quinases , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Humanos , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/química , Encéfalo/metabolismo , Camundongos , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , FemininoRESUMO
Chemoproteomics has made significant progress in investigating small-molecule-protein interactions. However, the proteome-wide profiling of cysteine ligandability remains challenging to adapt for high-throughput applications, primarily due to a lack of platforms capable of achieving the desired depth using low input in 96- or 384-well plates. Here, we introduce a revamped, plate-based platform which enables routine interrogation of either â¼18,000 or â¼24,000 reactive cysteines based on starting amounts of 10 or 20 µg, respectively. This represents a 5-10X reduction in input and 2-3X improved coverage. We applied the platform to screen 192 electrophiles in the native HEK293T proteome, mapping the ligandability of 38,450 reactive cysteines from 8,274 human proteins. We further applied the platform to characterize new cellular targets of established drugs, uncovering that ARS-1620, a KRASG12C inhibitor, binds to and inhibits an off-target adenosine kinase ADK. The platform represents a major step forward to high-throughput proteome-wide evaluation of reactive cysteines.
Assuntos
Cisteína , Proteoma , Humanos , Proteoma/metabolismo , Cisteína/metabolismo , Ligantes , Células HEK293RESUMO
BACKGROUND: Fibromyalgia is a syndrome characterized by generalized chronic pain and tenderness in specific areas. Photobiomodulation therapy (PBMT) using low-level laser therapy and/or light emitting diode therapy is an electrophysical agent that can be used alone or together with a static magnetic field (PBMT-sMF) to promote analgesia in several health conditions. Little evidence exists regarding the effects of using PBMT and PBMT-sMF in patients with fibromyalgia; this evidence is conflicting. AIM: We aimed to investigate the effects of using PBMT-sMF versus a placebo on reduction of the degree-of-pain rating, impact of fibromyalgia, pain intensity, and satisfaction with treatment in patients with fibromyalgia. DESIGN: A prospectively registered, monocentric, randomized placebo-controlled trial, with blinding of patients, therapists, and assessors, was performed. SETTING: The study was conducted at the Laboratory of Phototherapy and Innovative Technologies in Health (LaPIT) in Brazil, between March and October 2020. POPULATION: Ninety female patients with fibromyalgia were randomized to undergo either PBMT-sMF (N.=45) or placebo (N.=45) treatment. METHODS: Patients from both groups received nine treatment sessions, three times a week, for 3 weeks. Clinical outcomes were collected at baseline, the end of treatment, and at the follow-up appointment 4 weeks post-treatment. The primary outcome was the degree-of-pain rating, measured by the reduction of the tender point count. RESULTS: A decrease in the degree-of-pain rating was observed in patients allocated to the PBMT-sMF group, decreasing the number of tender points when compared to placebo group at the end of treatment (P<0.0001) and at the follow-up assessment (P<0.0001). Patients did not report any adverse events. CONCLUSIONS: PBMT-sMF is superior to placebo, supporting its use in patients with fibromyalgia. CLINICAL REHABILITATION IMPACT: PBMT-sMF might be considered an important adjuvant to the treatment regimens of patients with fibromyalgia.
Assuntos
Dor Crônica , Fibromialgia , Terapia com Luz de Baixa Intensidade , Humanos , Feminino , Fibromialgia/radioterapia , Protocolos Clínicos , Campos MagnéticosRESUMO
Pain is the most common reason for physician consultations and the number one reason for missed work or school days is musculoskeletal pain. Pain management is utilized for easing the suffering and improving the Quality of Life of those living with chronic pain. Over the past several decades, physicians have become increasingly willing to prescribe opioids to manage pain. However, the opioid use can cause side effects as poor coordination, sedation, mood swings, depression, and anxiety combined with a dependence on the drugs. In the rehabilitation setting, patients benefit most when their health providers utilize a multimodal approach combining different types of therapies and when patients take on a significant role in optimal management of their own pain. The use of light as a therapeutic alternative form of medicine to manage pain and inflammation has been proposed to fill this void. Photobiomodulation therapy applied in the form of low-intensity Light Amplification by Stimulated Emission of Radiation (LASER) and light-emitting diode (LED) has been shown to reduce inflammation and swelling, promote healing, and reduce pain for an array of musculoskeletal conditions. There is evidence that photobiomodulation therapy reduces pain intensity in non-specific knee pain, osteoarthritis, pain post-total hip arthroplasty, fibromyalgia, temporomandibular diseases, neck pain, and low back pain. Therefore, the purpose of this paper was to present the up-to-dated evidence about the effects of low-intensity LASER and LED (photobiomodulation therapy) on pain control of the most common musculoskeletal conditions. We observed that the photobiomodulation therapy offers a non-invasive, safe, drug-free, and side-effect-free method for pain relief of both acute and chronic musculoskeletal conditions as well as fibromyalgia.
Assuntos
Dor Crônica , Fibromialgia , Terapia com Luz de Baixa Intensidade , Dor Musculoesquelética , Dor Crônica/terapia , Fibromialgia/terapia , Humanos , Inflamação , Lasers , Terapia com Luz de Baixa Intensidade/métodos , Dor Musculoesquelética/radioterapia , Manejo da Dor , Qualidade de VidaRESUMO
Selinexor, a covalent XPO1 inhibitor, is approved in the USA in combination with dexamethasone for penta-refractory multiple myeloma. Additional XPO1 covalent inhibitors are currently in clinical trials for multiple diseases including hematologic malignancies, solid tumor malignancies, glioblastoma multiforme (GBM), and amyotrophic lateral sclerosis (ALS). It is important to measure the target engagement and selectivity of covalent inhibitors to understand the degree of engagement needed for efficacy, while avoiding both mechanism-based and off-target toxicity. Herein, we report clickable probes based on the XPO1 inhibitors selinexor and eltanexor for the labeling of XPO1 in live cells to assess target engagement and selectivity. We used mass spectrometry-based chemoproteomic workflows to profile the proteome-wide selectivity of selinexor and eltanexor and show that they are highly selective for XPO1. Thermal profiling analysis of selinexor further offers an orthogonal approach to measure XPO1 engagement in live cells. We believe these probes and assays will serve as useful tools to further interrogate the biology of XPO1 and its inhibition in cellular and inâ vivo systems.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/farmacologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Antineoplásicos/química , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química , Proteína Exportina 1RESUMO
RATIONALE & OBJECTIVE: During the coronavirus disease 2019 (COVID-19) pandemic, patients receiving maintenance dialysis are a highly vulnerable population due to their comorbidities and circumstances that limit physical distancing during treatment. This study sought to characterize the risk factors for and outcomes following COVID-19 in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Maintenance dialysis patients in clinics of a midsize national dialysis provider that had at least 1 patient who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from February to June 2020. PREDICTORS: Demographics, dialysis characteristics, residence in a congregated setting, comorbid conditions, measurements of frailty, and use of selected medications. OUTCOMES: COVID-19, defined as having a positive SARS-CoV-2 test result, and all-cause mortality among those with COVID-19. ANALYTICAL APPROACH: Logistic regression analyses conducted to identify clinical characteristics associated with COVID-19 and risk factors associated with mortality among patients following COVID-19. RESULTS: 438 of 7948 (5.5%) maintenance dialysis patients developed COVID-19. Male sex, Black race, in-center dialysis (vs home dialysis), treatment at an urban clinic, residence in a congregate setting, and greater comorbidity were associated with contracting COVID-19. Odds of COVID-19 were 17-fold higher for those residing in a congregated setting (odds ratio [OR], 17.10 [95% CI, 13.51-21.54]). Of the 438 maintenance dialysis patients with COVID-19, 109 (24.9%) died. Older age, heart disease, and markers of frailty were associated with mortality. LIMITATIONS: No distinction was detected between symptomatic and asymptomatic SARS-CoV-2 positivity, with asymptomatic screening limited by testing capacity during this initial COVID-19 surge period. CONCLUSIONS: COVID-19 is common among patients receiving maintenance dialysis, particularly those residing in congregate settings. Among maintenance dialysis patients with COVID-19, mortality is high, exceeding 20%.
Assuntos
COVID-19 , Fragilidade , Cardiopatias/epidemiologia , Controle de Infecções/métodos , Falência Renal Crônica , Diálise Renal , Fatores Etários , Idoso , COVID-19/mortalidade , COVID-19/terapia , Comorbidade , Feminino , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Fragilidade/etiologia , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade , Casas de Saúde/estatística & dados numéricos , Diálise Renal/métodos , Diálise Renal/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Estados Unidos/epidemiologiaRESUMO
Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor ß (LXRß) as the target. Binding of the small molecule ligand stabilized LXRß, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRß. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRß, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway.
Assuntos
Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Receptores X do Fígado/metabolismo , Astrócitos/citologia , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , ProteômicaRESUMO
Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Imunidade Inata , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Idade de Início , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Domínio Catalítico , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Inflamação , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/metabolismo , Proteínas de Ligação a RNA/genética , Risco , Regulação para CimaRESUMO
Novel chemical biology probes linking a serine hydrolase-directed fluorophosphonate warhead and cereblon-binding pomalidomide were assessed for the degradation of serine hydrolases. A quantitative proteomics approach to detect degraded proteins revealed that, despite the engagement of â¼40 serine hydrolases, degradation was achieved for only a single serine hydrolase, lysophospholipase II (LYPLA2).
Assuntos
Corantes Fluorescentes/química , Hidrolases/análise , Fosfatos/química , Proteômica , Serina/análise , Talidomida/análogos & derivados , Corantes Fluorescentes/metabolismo , Hidrolases/metabolismo , Estrutura Molecular , Fosfatos/metabolismo , Serina/metabolismo , Talidomida/química , Talidomida/metabolismoRESUMO
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/imunologia , CamundongosRESUMO
Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Here, we extend these studies by performing a proteome-wide analysis of covalent targets of BIA 10-2474 metabolites. Using alkynylated probes for click chemistry-ABPP in human cells, we show that des-methylated metabolites of BIA 10-2474 covalently modify the conserved catalytic cysteine in aldehyde dehydrogenases, including ALDH2, which has been implicated in protecting the brain from oxidative stress-related damage. These findings indicate that BIA 10-2474 and its metabolites have the potential to inhibit multiple mechanistically distinct enzyme classes involved in nervous system function.
Assuntos
Amidoidrolases/antagonistas & inibidores , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Área Sob a Curva , Linhagem Celular Tumoral , Cromatografia Líquida , Química Click , Óxidos N-Cíclicos/metabolismo , Óxidos N-Cíclicos/farmacocinética , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Espectrometria de Massas , Piridinas/metabolismo , Piridinas/farmacocinéticaAssuntos
Prestação Integrada de Cuidados de Saúde/organização & administração , Pessoal de Saúde/organização & administração , Mão de Obra em Saúde/organização & administração , Falência Renal Crônica/terapia , Modelos Organizacionais , Organizações sem Fins Lucrativos/organização & administração , Diálise Renal , Eficiência Organizacional , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Equipe de Assistência ao Paciente/organização & administração , Resultado do TratamentoRESUMO
Conformationally strained trans-cyclooctenes (TCOs) engage in bioorthogonal reactions with tetrazines with second order rate constants that can exceed 106 M-1s-1. The goal of this study was to provide insight into the stability of TCO reagents and to develop methods for stabilizing TCO reagents for long-term storage. The radical inhibitor Trolox suppresses TCO isomerization under high thiol concentrations and TCO shelf-life can be greatly extended by protecting them as stable Ag(I) metal complexes. 1H NMR studies show that Ag-complexation is thermodynamically favorable but the kinetics of dissociation are very rapid, and TCOâ¢AgNO3 complexes are immediately dissociated upon addition of NaCl which is present in high concentration in cell media. The AgNO3 complex of a highly reactive s-TCO-TAMRA conjugate was shown to label a protein-tetrazine conjugate in live cells with faster kinetics and similar labeling yield relative to a 'traditional' TCO-TAMRA conjugate.
RESUMO
The leaders of 20th century kidney failure treatment took chances; 21st century leaders of integrated kidney care must do the same. Some risks are clinical, some are organizational, and some are financial. Decent and constructive leadership entails humility. A working practitioner is a better leader. Effective leaders empower their employees and collaborators to lead and encourage them to work together. Integrated kidney care leadership supports exchange of ideas within and among organizations, uninhibited by competitive considerations. ESRD Seamless Care Organizations lead us toward the kidney care of the future; they will be strengthened by expansion to include patients who have advanced kidney disease not yet requiring renal replacement therapy and patients treated by transplant. Adjustment of reimbursement policy to realign incentives will be essential to the long-term success of care coordination. Population health management, with downside risk for participating organizations, is the future of integrated kidney care. Critical goals for integrated kidney care are to delay or avoid dialysis; increase use of home dialysis, transplantation, nondialytic care, and hospice; and to improve end of life care. It's about the patients, stupid.
Assuntos
Previsões , Falência Renal Crônica/terapia , Liderança , Nefrologia/métodos , Terapia de Substituição Renal/normas , HumanosRESUMO
A photochemical synthesis of AgNO3 complexes of trans-cycloheptene (TCH) and trans-1-sila-4-cycloheptene (Si-TCH) derivatives is described. A low temperature flow photoreactor was designed to enable the synthesis of carbocyclic TCH derivatives due to their thermal sensitivity in the absence of metal coordination. Unlike the free carbocycles, TCH·AgNO3 complexes can be handled at rt and stored for weeks in the freezer (-18 °C). Si-TCH·AgNO3 complexes are especially robust, and are bench stable for days at rt, and for months in the freezer. X-ray crystallography was used to characterize a Si-TCH·AgNO3 complex for the first time. With decomplexation of AgNO3in situ, metal-free TCO and Si-TCH derivatives can engage in a range of cycloaddition reactions as well as dihydroxylation reactions. Computation was used to predict that Si-TCH would engage in bioorthogonal reactions that are more rapid than the most reactive trans-cyclooctenes. Metal-free Si-TCH derivatives were shown to display good stability in solution, and to engage in the fastest bioorthogonal reaction reported to date (k2 1.14 × 107 M-1 s-1 in 9 : 1 H2O : MeOH). Utility in bioorthogonal protein labeling in live cells is described, including labeling of GFP with an unnatural tetrazine-containing amino acid. The reactivity and specificity of the Si-TCH reagents with tetrazines in live mammalian cells was also evaluated using the HaloTag platform. The cell labeling experiments show that Si-TCH derivatives are best suited as probe molecules in the cellular environment.
Assuntos
Princípios Morais , Diálise Renal/ética , Insuficiência Renal Crônica/terapia , Tempo para o Tratamento/ética , Humanos , Cobertura do Seguro/economia , Cobertura do Seguro/ética , Cobertura do Seguro/tendências , Diálise Renal/economia , Diálise Renal/tendências , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/economia , Tempo para o Tratamento/economia , Tempo para o Tratamento/tendênciasRESUMO
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Neurite (Inflamação)/tratamento farmacológico , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/metabolismo , Biomarcadores , Química Encefálica/efeitos dos fármacos , Cães , Desenho de Fármacos , Descoberta de Drogas , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
In this issue of Cell Chemical Biology, Grossman et al. (2017) disclose a chemoproteomics-enabled strategy to identify the cysteine-reactive target(s) of the anti-cancer natural product withaferin A and then screen a cysteine-reactive fragment library to discover a covalent ligand for the same target.