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1.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
2.
Bioorg Chem ; 104: 104320, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142428

RESUMO

In the present study, we intend to synthesize a series of novel substituted phenyl azetidine-2-one sulphonyl derivatives. The entire set of derivatives 5 (a-t) were screened for in-vitro antibacterial, and antifungal activity, and among them eleven compounds were further screened for the antiviral activity to predict their efficacy against pathogenic viruses. Interestingly, compound 5d, 5e, 5f, 5h, 5i, and 5j showed similar or better antibacterial activity as compared to ampicillin (standard). Moreover, compounds 5h, 5i, 5j, and 5q showed good inhibitory activity against fungal strains whereas other derivatives had mild or diminished activity in comparison with standard drug clotrimazole. The antimicrobial study indicated that compounds having electron-withdrawing groups showed the highest activity. Interestingly, these tested compounds showed weak antiviral activity against Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Herpes simplex virus, Sindbis virus, Coxsackievirus B4, Yellow Fever virus, and Influenza B virus in HEL cell, Vero cell, and MDCK cell cultures. The findings of the present study might open new avenues to target human disease-causing deadly microbes and viruses.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antivirais/farmacologia , Azetidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antifúngicos/síntese química , Antivirais/síntese química , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus niger/efeitos dos fármacos , Azetidinas/síntese química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Chlorocebus aethiops , Cães , Escherichia coli/efeitos dos fármacos , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Células Vero , Vírus/efeitos dos fármacos
3.
Int Immunopharmacol ; 86: 106749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32645632

RESUMO

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.


Assuntos
Azetidinas/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Azetidinas/farmacologia , Betacoronavirus/metabolismo , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Resultado do Tratamento , Montagem de Vírus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
4.
J Med Chem ; 63(15): 8584-8607, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32667798

RESUMO

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Receptores CCR4/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Linhagem Celular Tumoral , Cães , Humanos , Macaca fascicularis , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Receptores CCR4/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
5.
Pharmacotherapy ; 40(8): 843-856, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32542785

RESUMO

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.


Assuntos
Azetidinas/farmacologia , Azetidinas/uso terapêutico , Infecções por Coronavirus/complicações , Inflamação/tratamento farmacológico , Inflamação/etiologia , Janus Quinases/antagonistas & inibidores , Pneumonia Viral/complicações , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Área Sob a Curva , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Interações Medicamentosas , Humanos , Interferon Tipo I/biossíntese , Taxa de Depuração Metabólica , Pandemias , Peptidil Dipeptidase A/biossíntese , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
7.
Parasit Vectors ; 13(1): 227, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375898

RESUMO

BACKGROUND: The safety and efficacy of a new spot-on formulation of selamectin plus sarolaner were evaluated for the treatment and control of natural flea infestations on cats in two non-randomised, multi-centre clinical trials conducted in 8 different locations in Queensland, Australia. METHODS: One hundred and four cats from 65 different households were enrolled across the two studies. Demographic characteristics of cats in the two studies were similar. The new spot-on formulation of selamectin and sarolaner was administered topically once a month for 3 consecutive months at a minimum dosage of 6 mg/kg selamectin (dose range 6-12 mg/kg) plus 1 mg/kg sarolaner (dose range 1-2 mg/kg). Cats were dosed on Days 0 (pre-treatment), 30 and 60 and physical examinations and flea counts were conducted on Days 0, 30, 60 and 90. Efficacy assessments were based on the percentage reduction in live flea counts post-treatment compared to Day 0. RESULTS: In Study A, at enrolment, primary cats had flea counts ranging from 6 to 107 (arithmetic mean 21.0). The selamectin and sarolaner spot-on formulation resulted in arithmetic mean efficacy of 98.0%, 100% and 100% on Days 30, 60 and 90, respectively. In Study B, at enrolment, primary cats had flea counts ranging from 6 to 22 (arithmetic mean 10.0). The selamectin and sarolaner spot-on formulation resulted in arithmetic mean efficacy of 99.7%, 100% and 100% on Days 30, 60 and 90, respectively. CONCLUSIONS: The new spot-on formulation of selamectin plus sarolaner topically administered at monthly intervals at the minimum dosage of 6.0 mg/kg selamectin and 1.0 mg/kg sarolaner was safe and highly effective against natural infestations of fleas under a range of geographical conditions, representative of both tropical and subtropical regions of Australia.


Assuntos
Antiparasitários , Gatos/parasitologia , Infestações por Pulgas/veterinária , Sifonápteros/efeitos dos fármacos , Administração Tópica , Animais , Antiparasitários/administração & dosagem , Antiparasitários/farmacologia , Austrália , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Doenças do Gato/tratamento farmacológico , Infestações por Pulgas/tratamento farmacológico , Inseticidas/administração & dosagem , Inseticidas/farmacologia , Ivermectina/administração & dosagem , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologia , Resultado do Tratamento
8.
EMBO Mol Med ; 12(8): e12697, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32473600

RESUMO

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.


Assuntos
Antivirais/farmacologia , Inteligência Artificial , Azetidinas/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/farmacologia , Adulto , Idoso , Antivirais/farmacocinética , Antivirais/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Citocinas/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Fígado , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/virologia , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
9.
Molecules ; 25(6)2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32245167

RESUMO

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal-to design an entry inhibitor with improved drug-like qualities-and warrants expanded studies to achieve this.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfatos/química , Piperazinas/química , Triazóis/metabolismo , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Cromatografia Líquida , Células HEK293 , Proteína do Núcleo p24 do HIV/química , Proteína do Núcleo p24 do HIV/metabolismo , Inibidores da Fusão de HIV/metabolismo , Infecções por HIV/virologia , Humanos , Microssomos Hepáticos/virologia , Organofosfatos/farmacologia , Piperazinas/farmacologia , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Espectrometria de Massas em Tandem , Triazóis/síntese química , Triazóis/farmacologia , Triazóis/toxicidade
10.
J Med Chem ; 63(9): 4997-5010, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32338903

RESUMO

Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Azetidinas/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos SCID , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Arch Oral Biol ; 113: 104707, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32197133

RESUMO

OBJECTIVE: Fatty acid synthase (FASN) is overexpressed in several human cancers, including oral squamous cell carcinoma (OSCC). TVB-3166 is a recently described FASN inhibitor with antitumor effects and potential clinical relevance. The objective of this study was to evaluate the effects of TVB-3166 on OSCC cell lines. MATERIALS AND METHODS: The OSCC cell line SCC-9 modified to express ZsGreen (ZsG) (SCC-9 ZsG) and its in vivo selected metastatic derivative LN-1A were used to evaluate anticancer properties of TVB-3166. Cell viability was determined using MTT assays and proliferation determined by cell counting in a Neubauer chamber. Cell death and cell cycle progression were analyzed by Annexin V-PE/7-ADD-PerCP labeling and PI staining, respectively. Cell migration was assayed by scratch assays and cell adhesion using myogel. Production of FASN, p-AKT, CPT1-α, and epithelial-mesenchymal transition (EMT) markers were examined by Western blotting. RESULTS: TVB-3166 significantly reduced cell viability and proliferation, promoted cell cycle arrest and apoptosis, and increased adhesion to myogel in both OSCC cell lines. Finally, the drug reduced SCC-9 ZsG migration. CONCLUSION: Our results demonstrated that TVB-3166 has anticancer effects on both SCC-9 ZsG and its metastatic version LN-1A, which are worthy of investigation in preclinical models for OSCC.


Assuntos
Azetidinas/farmacologia , Carcinoma de Células Escamosas/patologia , Ácido Graxo Sintases/antagonistas & inibidores , Neoplasias Bucais/patologia , Nitrilos/farmacologia , Pirazóis/farmacologia , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Bucais/tratamento farmacológico
12.
Expert Opin Pharmacother ; 21(9): 1027-1033, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32208940

RESUMO

INTRODUCTION: Moderate-to-severe AD burdens a large proportion of AD patients and may represent an inadequacy of treatment options available for resistant disease. AREAS COVERED: This review provides an overview of the therapies for moderate-to-severe AD in late-stage development and in the clinic, and focuses on baricitinib as an emerging therapeutic option. Baricitinib is an orally available selective JAK1/JAK2 inhibitor that is approved for use in the treatment of moderate-to-severe rheumatoid arthritis (RA). Baricitinib decreases AD lesions, disease severity, and improves quality of life. Overall, the small molecule inhibitor is well tolerated. However, its black-box warnings in the RA population raise a concern for its long-term safety. EXPERT OPINION: Baricitinib is a promising treatment modality for moderate-to-severe AD. Its primary advantage over dupilumab, the revolutionary biologic agent approved for AD, is that patients prefer an oral medication over an injection. However, providers will likely prescribe an injectable over an oral medication if baricitinib has an unfavorable safety profile. Insurance coverage of baricitinib will also have a major role in clinical use. Baricitinib will likely face competition from other JAK inhibitors in the future; however, it will have an advantage if it becomes the first FDA-approved medication of its kind for resistant AD.


Assuntos
Azetidinas/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Azetidinas/farmacologia , Método Duplo-Cego , Humanos , Inibidores de Janus Quinases/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/farmacologia
13.
Biol Pharm Bull ; 43(2): 325-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009119

RESUMO

Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.


Assuntos
Azetidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Artrite Experimental/tratamento farmacológico , Azetidinas/farmacocinética , Células Cultivadas , Citocinas/sangue , Citocinas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Ratos Endogâmicos Lew , Receptor trkA/metabolismo
14.
Org Biomol Chem ; 18(16): 3069-3081, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32101243

RESUMO

The use of selective covalent inhibitors with low binding affinity and high reactivity with the target enzyme is a promising way to solve a long-standing problem of the "undruggable" RAS-like proteins. Specifically, compounds of the ARS family that prevent the activation of the GDP-bound G12C mutant of Kirsten RAS (KRAS) are in the focus of recent experimental research. We report the first computational characterization of the entire reaction mechanism of the covalent binding of ARS-853 to the KRASG12C·GDP complex. The application of molecular dynamics, molecular docking and quantum mechanics/molecular mechanics approaches allowed us to model the inhibitor binding to the protein and the chemical reaction of ARS-853 with Cys12 in the enzyme binding site. We estimated a full set of kinetic constants and carried out numerical kinetic analysis of the process. Thus, we were able to compare directly the physicochemical parameters of the reaction obtained in silico and the macroscopic parameters observed in experimental studies. From our computational results, we explain the observed unusual dependence of the rate constant of covalent complex formation, kobs, on the ARS concentration. The latter depends both on the non-covalent binding step with the equilibrium constant, Ki, and on the rate constant of covalent adduct formation, kinact. The calculated ratio kinact/Ki = 213 M-1 s-1 reproduces the corresponding experimental value of 250 ± 30 M-1 s-1 for the interaction of ARS-853 with KRASG12C. Electron density analysis in the reactive region demonstrates that covalent bond formation occurs efficiently according to the Michael addition mechanism, which assumes the activation of the C[double bond, length as m-dash]C bond of ARS-853 by a water molecule and Lys16 in the binding site of KRASG12C. We also refine the kinact and Ki constants of the ARS-107 compound, which shares common features with ARS-853, and show that the decrease in the kinact/Ki ratio in the case of ARS-107 is explained by changes in both Ki and kinact constants.


Assuntos
Azetidinas/metabolismo , Piperazinas/metabolismo , Proteínas ras/antagonistas & inibidores , Azetidinas/farmacologia , Sítios de Ligação , Guanosina Difosfato/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Mutação , Piperazinas/farmacologia , Estudo de Prova de Conceito , Ligação Proteica , Proteínas ras/efeitos dos fármacos , Proteínas ras/genética , Proteínas ras/metabolismo
15.
Arch Pharm (Weinheim) ; 353(3): e1900293, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917485

RESUMO

A new series of 1,4-diarylazetidin-2-one derivatives (ß-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized ß-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the ß-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.


Assuntos
Analgésicos/farmacologia , Azetidinas/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dor/tratamento farmacológico , beta-Lactamas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Azetidinas/síntese química , Azetidinas/química , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/química
16.
Lipids Health Dis ; 18(1): 234, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883528

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined. METHODS: To achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated. RESULTS: Unlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2 weeks, there were no significant differences in the hepatic expression of Pparα, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P < 0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor. CONCLUSION: Hepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis.


Assuntos
VLDL-Colesterol/genética , Fígado Gorduroso/genética , Reabsorção Intestinal/genética , Proteínas de Membrana Transportadoras/genética , Animais , Azetidinas/farmacologia , Bile/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ezetimiba/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Triglicerídeos/genética
17.
PLoS One ; 14(10): e0224600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671149

RESUMO

Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS pathway and a therapeutic target in RAS-driven cancers. Although tumor responses to MEK inhibition are rarely durable, MEK inhibitors have shown substantial activity and durable tumor regressions when combined with systemic immunotherapies in preclinical models of RAS-driven tumors. MEK inhibitors have been shown to potentiate anti-tumor T cell immunity, but little is known about the effects of MEK inhibition on other immune subsets, including B cells. We show here that treatment with a MEK inhibitor reduces B regulatory cells (Bregs) in vitro, and reduces the number of Bregs in tumor draining lymph nodes in a colorectal cancer model in vivo. MEK inhibition does not impede anti-tumor humoral immunity, and B cells contribute meaningfully to anti-tumor immunity in the context of MEK inhibitor therapy. Treatment with a MEK inhibitor is associated with improved T cell infiltration and an enhanced response to anti-PD1 immunotherapy. Together these data indicate that MEK inhibition may reduce Bregs while sparing anti-tumor B cell function, resulting in enhanced anti-tumor immunity.


Assuntos
Linfócitos B Reguladores/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Animais , Azetidinas/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes ras/efeitos dos fármacos , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Expert Opin Investig Drugs ; 28(12): 1051-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31603362

RESUMO

Introduction: Multiple sclerosis (MS) causes focal lesions of immune-mediated demyelinating events followed by slow progressive accumulation of disability. Over the past 2 decades, multiple medications have been studied and approved for use in MS. Most of these agents work by modulating or suppressing the peripheral immune system. Siponimod is a newer-generation sphingosine 1 phosphate (S1P) receptor modulator that internalizes S1P1 receptors, thereby inhibiting efflux of lymphocytes from lymph nodes and thymus. There are promising data suggesting that it may also have a direct neuroprotective property independent of peripheral lymphocytopenia.Areas covered: We reviewed the pharmacology and the clinical and radiological effects of siponimod.Expert opinion: The selective effect of siponimod on the S1P1 and S1P5 receptors offers a favorable side-effect profile and transient bradycardia can be avoided by dose titration. A phase-II study showed that siponomod has dose-dependent beneficial effects in patients with relapsing remitting disease. The results of a phase-III study suggest that siponimod may be beneficial in secondary progressive MS, at least in patients with disease activity.


Assuntos
Azetidinas/administração & dosagem , Compostos de Benzil/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/administração & dosagem , Animais , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Compostos de Benzil/efeitos adversos , Compostos de Benzil/farmacologia , Relação Dose-Resposta a Droga , Humanos , Esclerose Múltipla/fisiopatologia , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacos , Receptores de Esfingosina-1-Fosfato/metabolismo
19.
Stroke ; 50(11): 3246-3254, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31558140

RESUMO

Background and Purpose- Perihemorrhagic edema (PHE) is associated with poor outcome after intracerebral hemorrhage (ICH). Infiltration of immune cells is considered a major contributor of PHE. Recent studies suggest that immunomodulation via S1PR (sphingosine-1-phosphate receptor) modulators improve outcome in ICH. Siponimod, a selective modulator of sphingosine 1-phosphate receptors type 1 and type 5, demonstrated an excellent safety profile in a large study of patients with multiple sclerosis. Here, we investigated the impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH. Methods- ICH was induced by intracranial injection of 0.075 U of bacterial collagenase in 123 mice. Mice were randomly assigned to different treatment groups: vehicle, siponimod given as a single dosage 30 minutes after the operation or given 3× for 3 consecutive days starting 30 minutes after operation. The primary outcome of our study was evolution of PHE measured by magnetic resonance-imaging on T2-maps 72 hours after ICH, secondary outcomes included evolution of PHE 24 hours after ICH, survival and neurological deficits, as well as effects on circulating blood cells and body weight. Results- Siponimod significantly reduced PHE measured by magnetic resonance imaging (P=0.021) as well as wet-dry method (P=0.04) 72 hours after ICH. Evaluation of PHE 24 hours after ICH showed a tendency toward attenuated brain edema in the low-dosage group (P=0.08). Multiple treatments with siponimod significantly improved neurological deficits measured by Garcia Score (P=0.03). Survival at day 10 was improved in mice treated with multiple dosages of siponimod (P=0.037). Mice treated with siponimod showed a reduced weight loss after ICH (P=0.036). Conclusions- Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in our experimental ICH-model. Findings encourage further investigation of inflammatory modulators as well as the translation of BAF-312 to a human study of ICH patients.


Assuntos
Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Edema Encefálico , Hemorragia Cerebral , Transdução de Sinais/efeitos dos fármacos , Animais , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Receptores de Esfingosina-1-Fosfato/metabolismo
20.
J Neuroinflammation ; 16(1): 182, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31561750

RESUMO

BACKGROUND: Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/ß, and other pro-inflammatory cytokines. METHODS: Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS: In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. CONCLUSION: These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.


Assuntos
Complexo AIDS Demência/patologia , Complexo AIDS Demência/virologia , Azetidinas/farmacologia , Sulfonamidas/farmacologia , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos SCID , Latência Viral/efeitos dos fármacos
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