RESUMO
BACKGROUND: Occlusive treatments are a mainstay in atopic dermatitis (AD) management but may not be well tolerated or lack compliance. A comfortable, semiocclusive, artificial skin barrier that is well tolerated, provides protection, and reduces water loss is needed. OBJECTIVE: To evaluate the potential tolerability and therapeutic benefits of a crosslinked polymer layer (XPL) in adults with AD. METHODS: A single-center, open-label pilot study was conducted involving 10 subjects with moderate to severe AD. Subjects applied XPL up to twice daily for 30 days on a selected treatment area. Investigator's Global Assessment, clinical signs of eczema, and pruritus were assessed on days 1, 3, 5, 15, and 30. Film durability and patient satisfaction were also evaluated. RESULTS: Investigator's Global Assessment scores improved from moderate to severe at baseline to clear to almost clear in 8 of 9 patients at day 30. Pruritus improved from trace to severe itching (baseline) to all subjects having trace to no itching at day 30. There was 1 adverse event of mild exudative dermatitis. LIMITATIONS: The study was limited by small sample size, open-label design, and lack of control. CONCLUSION: XPL may be an effective adjuvant in AD treatment. A larger study with a control group is warranted.
Assuntos
Dermatite Atópica/terapia , Curativos Oclusivos , Polímeros/administração & dosagem , Prurido/terapia , Administração Cutânea , Adulto , Reagentes de Ligações Cruzadas , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polímeros/química , Prurido/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.
Assuntos
Aminoimidazol Carboxamida/síntese química , Aminoimidazol Carboxamida/farmacologia , Janus Quinase 2/antagonistas & inibidores , Tiofenos/síntese química , Tiofenos/farmacologia , Aminoimidazol Carboxamida/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Modelos Biológicos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Tiofenos/químicaRESUMO
This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridonas/química , Sulfonamidas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Janus Quinase 2/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Janus Quinase 2/antagonistas & inibidores , Piridonas/química , Animais , Sítios de Ligação , Simulação por Computador , Ciclização , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Piridonas/síntese química , Piridonas/farmacologia , Fator de Transcrição STAT5/metabolismo , Relação Estrutura-AtividadeRESUMO
A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617âPhe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.