RESUMEN
The relaxant effect of an aryloxypropanolamine ß3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hß3-AR agonists have been evaluated and discussed thoroughly. A ranking of hß3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Propanolaminas/farmacología , Receptores Adrenérgicos beta 3/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Acetanilidas/farmacología , Anciano , Compuestos de Anilina/farmacología , Benzoatos/farmacología , Compuestos de Bifenilo , Carbacol/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Técnicas In Vitro , Ligandos , Masculino , Músculo Liso/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Tiazoles/farmacología , Vejiga Urinaria/metabolismoRESUMEN
Resulting from a vHTS based on a pharmacophore alignment on known ß3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ß3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hß1- and hß2-adrenoceptors and a promising safety profile.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 3/química , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/síntesis química , Línea Celular , Supervivencia Celular , Diseño de Fármacos , Humanos , Unión Proteica , Pirimidinas/síntesis químicaRESUMEN
Using a vHTS based on a pharmacophore alignment on known beta3-adrenoceptor ligands, a set of intriguing beta-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human beta2-AR antagonist.
Asunto(s)
Receptores Adrenérgicos beta/metabolismo , Semivida , Humanos , Enlace de Hidrógeno , Ligandos , Modelos MolecularesRESUMEN
Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Aurora Quinasas , Línea Celular Tumoral , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
New structural classes of K(V)1.3 and IK-1 ion channel blockers have been identified based on a virtual high throughput screening approach using a homology model of KcsA. These compounds display inhibitory effects on T-cell and/or keratinocyte proliferation and immunosuppressant activity within a DTH animal model.
Asunto(s)
Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Canal de Potasio Kv1.3/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/metabolismo , Inmunosupresores/clasificación , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/química , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/fisiología , Queratinocitos/efectos de los fármacos , Queratinocitos/fisiología , Canal de Potasio Kv1.3/química , Canal de Potasio Kv1.3/fisiología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/clasificaciónRESUMEN
Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC(50) values in the nanomolar range on different kinases down to 63nM.
Asunto(s)
Benzotiazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Benzotiazoles/metabolismo , Sitios de Unión/fisiología , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
Based on a pharmacophore alignment on a 5-HT(6) ligand applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)s down to 8 nM were achieved.
Asunto(s)
Compuestos de Anilina/química , Simulación por Computador , Piperazinas/química , Receptores de Serotonina/química , Sulfonamidas/química , Compuestos de Anilina/farmacología , Diseño de Fármacos , Humanos , Indoles/química , Indoles/farmacología , Ligandos , Modelos Moleculares , Estructura Molecular , Piperazina , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Programas Informáticos , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.
Asunto(s)
Amidas/química , Compuestos de Bifenilo/química , Ácidos Dicarboxílicos/química , Modelos Moleculares , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Sitios de Unión , Cristalografía por Rayos X , Dihidroorotato Deshidrogenasa , Humanos , Estructura Molecular , Unión Proteica , Ubiquinona/químicaRESUMEN
A previously discovered DHODH inhibitor series was further improved by replacing the cyclopentene ring by aromatic heterocycles. Different isomers of these compounds were prepared by the directed ortho-metallation procedure. The compounds are more active than the corresponding cyclopentene analogs and show potent effects on PBMC's proliferation.
Asunto(s)
Compuestos de Bifenilo/farmacología , Carbamatos/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Tiofenos/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Carbamatos/síntesis química , Carbamatos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Dihidroorotato Deshidrogenasa , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
Based on a pharmacophore alignment on known non-competitive mGluR5 inhibitors applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)'s as low as around 100 nM were achieved.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Antagonistas de Aminoácidos Excitadores/química , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
Results from aromatic aminations and Kumada couplings, together with spectroscopic analyses (TEM, EDX, ICP-AES, React-IR), reveal that catalysis using nickel-on-charcoal (Ni/C) is most likely of a homogeneous rather than heterogeneous nature. In the course of a reaction with Ni/C, nickel bleed from the support was calculated to be as high as 78%. However, the existence of an equilibrium for this homogeneous species between nickel located inside vs outside the pore system of charcoal strongly favors the former, thus leaving only traces of metal detectable in solution. This accounts for virtually complete recovery of nickel on the charcoal following filtration of a reaction mixture and allows for recycling of the catalyst. TEM and EDX data were used to explain different reactivity profiles of Ni/C, which depended upon the method of reduction used to convert Ni(II)/C to Ni(0) as well as the level of nickel loading on the support.
Asunto(s)
Carbón Orgánico/química , Níquel/química , Aminación , Catálisis , Filtración , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Microscopía Electrónica , Estructura Molecular , Morfolinas/química , Níquel/análisis , Oxidación-Reducción , Soluciones/químicaRESUMEN
Protocols for aromatic aminations and Kumada couplings catalyzed by 'heterogeneous' nickel-on-charcoal (Ni/C) have been revised, making them simpler and more time efficient. For both types of reactions, reduction of the catalyst precursor Ni(II)/C using n-BuLi prior to addition of a substrate can be avoided. Instead, in amination reactions, the amine in combination with lithium tert-butoxide was found to convert Ni(II)/C to active Ni(0). For Kumada couplings, direct reduction of Ni(II)/C by the Grignard reagent is easily achieved. Reactions run in the presence of triarylphosphine ligands of varying substitution patterns and with differing electronic properties provided insight into the mechanism of these nickel-catalyzed transformations. Ligandless Kumada couplings were facile with aryl Grignards, which may be a consequence of pi-complexation of nickel by the aryl group in the reagent. Larger scale reactions of both types of couplings have been successfully performed, suggesting that Ni/C-based processes can be scaled-up as needed.
Asunto(s)
Carbón Orgánico/química , Hidrocarburos Aromáticos/química , Níquel/química , Aminación , Catálisis , Filtración , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Morfolinas/química , Níquel/análisis , Oxidación-Reducción , Soluciones/químicaRESUMEN
The structurally and pharmacologically intriguing but stereochemically initially disregarded small class of biarylic biscarbazole alkaloids is presented, starting with an introduction of the different structural patterns found in nature. For the construction of the biaryl bond, mainly biomimetic oxidative coupling reactions were used, as shown for the natural products bismurrayaquinone-A, bis-2-hydroxy-3-methylcarbazole, clausenamine-A, and murrastifoline-F. For most of these compounds, a resolution of the respective atropo-enantiomers succeeded either directly, by high-performance liquid chromatography by HPLC on a chiral phase, or via atropo-diastereomers, after derivatization with a chiral auxiliary. The absolute configurations of the pure enantiomers were assigned by comparison of experimental (CD) spectra with those quantum chemi-cally calculated, or, for atropo-diastereomeric derivatives, by means of ROESY investigations and X-ray crystallography. Ullmann-type coupling conditions were also found to be feasible for the construction of the 2,2'-biscarbazole core, necessitating a completely regioselective 2-bromination protocol. The first atroposelective synthesis of such a basic target structure was achieved by application of the "lactone methodology," giving rise to an atropisomeric ratio of 85 : 15. Some of the biscarbazole alkaloids and their derivatives were found to have interesting bioactivities, and for the first time, the natural atropo-enantiomeric ratio in the plants was determined for one of these compounds, murrastifoline-F.