RESUMEN
The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Activados por la Liberación de Calcio/antagonistas & inhibidores , Calcio/metabolismo , Descubrimiento de Drogas , Administración Oral , Animales , Área Bajo la Curva , Artritis Reumatoide/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/farmacocinética , Ensayos Clínicos Fase I como Asunto , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
The first "In Water" imidazolecarbonylation of amine is described. A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates. Use of an anhydrous solvent and an inert atmosphere could be avoided. Product precipitate out from the reaction mixture and can be obtained in high purity by filtration, resulting in a simple and scalable method.
Asunto(s)
Aminas/química , Carbamatos/síntesis química , Imidazoles/química , Tiocarbamatos/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Agua/química , Carbamatos/química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Tiocarbamatos/química , Urea/químicaRESUMEN
A new method for the oxidation of nucleoside phosphite triester into phosphate triester under nonbasic and nonaqueous conditions using NBS-DMSO in CH(3)CN has been developed. The utility of this method for solution- and solid-phase synthesis of oligonucleotide is demonstrated.
Asunto(s)
Dimetilsulfóxido/química , Oligonucleótidos/síntesis química , Cromatografía Líquida de Alta Presión , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Oxidación-ReducciónRESUMEN
The mixture of carbon tetrachloride, N-methyl morpholine (NMM), pyridine and water in acetonitrile has been exploited for the oxidation of dinucleoside H-phosphonate diesters to the corresponding phosphates. The system is found to be inert to the phosphoramidate (P-N) and the phosphorothioate (P-S) linkages and has successfully been applied to the solid phase synthesis of mixed-backbone oligonucleotides (MBOs).
