RESUMEN
Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.
Asunto(s)
Enfermedades del Sistema Inmune , Inhibidores de las Cinasas Janus , Benzamidas , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéuticoRESUMEN
Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.
Asunto(s)
Antirreumáticos/farmacología , Artritis Experimental/tratamiento farmacológico , Descubrimiento de Drogas , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Antirreumáticos/síntesis química , Antirreumáticos/química , Artritis Experimental/sangre , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 3/sangre , Janus Quinasa 3/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
UNLABELLED: Abstract Context: Tumor necrosis factor (TNF)-α, a potent proinflammatory cytokine, plays a major role in the pathogenesis of cancer. TNF-α converting enzyme (TACE) mediates processing and release of biologically active TNF-α. OBJECTIVE: We aimed to investigate the effect of a novel, selective TACE inhibitor (compound 11p) on skin inflammation and associated tumorigenesis in mice. METHODS: Skin edema was induced in mice by dermal application 12-O-tetradecanoylphorbol-13-acetate (TPA) solution in acetone on to the ear and the effect of post-treatment of compound 11p (topical application) was evaluated. Edema and inflammation was assessed by measuring ear thickness, weight of skin punch and cytokine levels. Skin cancer in mice was initiated by single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by repeated TPA application for 20 weeks. The effect of compound 11p on papilloma incidence and multiplicity was evaluated. RESULTS: Treatment with compound 11p strongly suppressed TPA-induced elevation in skin thickness and weight. A dose-dependent suppression in TPA-mediated TNF-α, IL-6, IFN-γ, IL-17 and PGE2 levels which was associated with a decrease in infiltration of inflammatory cells was also observed with the treatment. Moreover, compound 11p treatment delayed the onset, markedly reduced the papilloma incidence and multiplicity persuaded by DMBA and TPA. DISCUSSION AND CONCLUSION: These findings suggest that selective blockade of TACE suppresses TPA-induced epidermal hyperplasia, inflammatory cell infiltration and cytokine level. Inhibition of inflammatory events related to tumor growth might have led to the anti-tumor effect in mouse skin cancer model induced by DMBA and TPA.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/toxicidad , Proteínas ADAM/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Pirrolidinonas/uso terapéutico , Neoplasias Cutáneas/prevención & control , Acetato de Tetradecanoilforbol/toxicidad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteína ADAM17 , Animales , Antineoplásicos/administración & dosificación , Cocarcinogénesis , Citocinas/inmunología , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Edema/inmunología , Edema/patología , Femenino , Ácidos Hidroxámicos/administración & dosificación , Ratones Endogámicos BALB C , Pirrolidinonas/administración & dosificación , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1ß, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.