RESUMEN
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Asunto(s)
Antifúngicos/química , Inhibidores Enzimáticos/química , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Sulfonamidas/química , Animales , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Glucosiltransferasas/metabolismo , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Asunto(s)
Antiinflamatorios/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/síntesis química , Inhibidores de Fosfodiesterasa 4/síntesis química , Quinolinas/síntesis química , Animales , Antiinflamatorios/farmacología , Óxidos N-Cíclicos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Oxazoles/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/síntesis química , Piridazinas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Inhibidores Enzimáticos/química , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Piridazinas/farmacología , Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Relación Estructura-ActividadRESUMEN
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.
Asunto(s)
Oxazoles/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/efectos de los fármacos , Modelos Moleculares , Oxazoles/química , Inhibidores de Fosfodiesterasa/química , RatasRESUMEN
Packed-column supercritical fluid chromatography (pSFC) coupled to an atmospheric pressure chemical ionization (APCI) source and a tandem mass spectrometer (MS/MS) for rapid and simultaneous determination of clozapine, ondansetron, tolbutamide and primidone in in vitro samples was developed in support of metabolic stability experiments. The effects of the eluent flow-rate and composition as well as the nebulizer temperatures on the ionization efficiency of the analytes in positive ion mode under normal phase pSFC conditions were studied. The metabolic stability of the test drug components through microsomal incubation by the proposed pSFC-APCI/MS/MS approaches requiring approximately 1 min per samples were evaluated with respect to specificity, durability and accuracy. These metabolic stability results obtained by pSFC-MS/MS methods are in a good agreement with those obtained by fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.
Asunto(s)
Preparaciones Farmacéuticas/análisis , Animales , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Técnicas In Vitro , Indicadores y Reactivos , Espectrometría de Masas , Microsomas Hepáticos/metabolismo , Preparaciones Farmacéuticas/metabolismo , RatasRESUMEN
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Piperidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP2D6 , Evaluación Preclínica de Medicamentos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Técnicas In Vitro , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Asunto(s)
Ansiolíticos/química , Ansiolíticos/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Urea/análogos & derivados , Urea/farmacología , Animales , Ansiolíticos/síntesis química , Alcoholes Bencílicos/química , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Flúor/química , Gerbillinae , Modelos Moleculares , Estructura Molecular , Actividad Motora/efectos de los fármacos , Relación Estructura-Actividad , Urea/síntesis químicaRESUMEN
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Urea/análogos & derivados , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Gerbillinae , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Actividad Motora/efectos de los fármacos , Unión Proteica , Ratas , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK(1)/NK(2) antagonists.