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1.
Bioorg Med Chem Lett ; 20(16): 4819-24, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20663667

RESUMEN

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.


Asunto(s)
Amidas/química , Antiinflamatorios no Esteroideos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Sitio Alostérico , Amidas/síntesis química , Amidas/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacocinética , Sitios de Unión , Línea Celular , Simulación por Computador , Humanos , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
2.
Eur J Pharmacol ; 632(1-3): 93-102, 2010 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-20132813

RESUMEN

The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Administración Oral , Animales , Artritis Reumatoide/tratamiento farmacológico , Benzamidas/antagonistas & inhibidores , Benzamidas/química , Células Cultivadas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Inflamación/tratamiento farmacológico , Lipopolisacáridos/antagonistas & inhibidores , Macrófagos/metabolismo , Masculino , Modelos Químicos , Modelos Inmunológicos , Modelos Moleculares , Monocitos/metabolismo , Morfolinas/antagonistas & inhibidores , Morfolinas/química , Osteoporosis/tratamiento farmacológico , Osteoporosis/inmunología , Osteoporosis/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
4.
J Chromatogr A ; 1194(2): 172-7, 2008 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-18486137

RESUMEN

Astaxanthin (3,3'-dihydroxy-beta,beta-carotene-4,4'-dione) is widely used as important colorant in the aquaculture feed industry, and as nutraceuticals in human health products. Synthetic all-trans-astaxanthin consists of a mixture of a pair of enantiomers (3R,3'R and 3S,3'S) and a mesoform (3R,3'S). A high-performance liquid chromatography (HPLC) method for direct, rapid, and baseline separation of three stereoisomers of all-trans-astaxanthin is described for the first time on an immobilized cellulosic column (Chiralpak IC). Enantiomers of two important precursors in the biosynthetic pathway of astaxanthin, adonirubin and adonixanthin, were also directly separated. In addition, the major cis form of astaxanthin (13-cis-astaxanthin) resulted from isomerization was isolated with preparative C18 separation, and the separation of all four stereoisomers of 13-cis-astaxanthin is achieved. Finally, a stereoisomeric purity test of commercial astaxanthin supplements confirmed that they were from a natural source, although their levels were quite low.


Asunto(s)
Carotenoides/aislamiento & purificación , Carotenoides/química , Cromatografía Líquida de Alta Presión , Estructura Molecular , Estereoisomerismo , Xantófilas/química , Xantófilas/aislamiento & purificación
5.
Bioorg Med Chem Lett ; 18(6): 1772-7, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18325768
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