RESUMEN
Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5â³, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridonas/química , Piridonas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Halogenación , HumanosRESUMEN
Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.
Asunto(s)
Benzoatos/síntesis química , Lactamas/síntesis química , Pirrolidinas/síntesis química , Receptores de Prostaglandina E/agonistas , Animales , Benzoatos/farmacocinética , Benzoatos/farmacología , Proteínas Sanguíneas/metabolismo , Semivida , Humanos , Lactamas/farmacocinética , Lactamas/farmacología , Modelos Moleculares , Conformación Molecular , Método de Montecarlo , Oxidación-Reducción , Unión Proteica , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Optimization of the amino acid side chain and the N-alkyl group of the sulfonamide of amino acid derived sulfonamide hydroxamates is discussed. The solid-phase synthesis of these potent inhibitors of procollagen C-proteinase (PCP) is presented. In addition, novel carboxylic acid sulfonamides were discovered to be PCP inhibitors.
Asunto(s)
Aminoácidos/química , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Proteína Morfogenética Ósea 1 , Ácidos Hidroxámicos/química , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic data are discussed.
Asunto(s)
Antirreumáticos/síntesis química , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Antirreumáticos/química , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.