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1.
Bioorg Med Chem Lett ; 29(12): 1522-1531, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-30981576

RESUMEN

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).


Asunto(s)
Dermatitis Atópica/genética , Interleucina-13/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Humanos , Transducción de Señal
3.
J Med Chem ; 58(20): 8182-99, 2015 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-26431428

RESUMEN

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.


Asunto(s)
Encéfalo/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Animales , Barrera Hematoencefálica , Descubrimiento de Drogas , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Enfermedades Neurodegenerativas/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Difracción de Rayos X
4.
J Med Chem ; 57(5): 2033-46, 2014 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-24320933

RESUMEN

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.


Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Secuencia de Bases , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Cartilla de ADN , Método Doble Ciego , Fluorenos/farmacocinética , Fluorenos/farmacología , Semivida , Humanos , Macaca fascicularis , Masculino , Placebos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
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