RESUMEN
Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 µM) and cell-free assays (IC50 values 0.03 µM) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Antagonistas de Leucotrieno/farmacología , Leucotrienos/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Tiazoles/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Antagonistas de Leucotrieno/síntesis química , Antagonistas de Leucotrieno/química , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
A series of benzo[b]furan derivatives having a five-membered heterocyclic substituent at the 2-position were prepared from 2-(1-chloro-2-formylvinyl)benzo[b]furans (2) and 2-(4-alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans. These 2-heterocyclic benzo[b]furans were evaluated for their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity. Several compounds showed moderate inhibition of calcium mobilization in HEK 293T-cysLT2 or CHO-cysLT1 cells.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Receptores de Leucotrienos/metabolismo , Animales , Benzofuranos/síntesis química , Células CHO , Calcio/metabolismo , Cricetinae , Células HEK293 , Humanos , Antagonistas de Leucotrieno/síntesis químicaRESUMEN
The pharmacophore model (Hypo1) with a well prediction capacity for CysLT(1) antagonists was developed using Catalyst/HypoGen program. Virtual screening against an in-house database consisted of carboxylated chalcones using Hypo1 was performed. Retrieved hits 26a, 26b, 27a, and 27b were synthesized and biological evaluated, the results of which demonstrated that these compounds showed moderate to good CysLT(1) antagonistic activities. This study indicated that the generated model (Hypo1) is a reliable and useful tool in lead optimization for novel CysLT(1) antagonists.
Asunto(s)
Chalcona/química , Antagonistas de Leucotrieno/síntesis química , Receptores de Leucotrienos/química , Línea Celular Tumoral , Chalcona/síntesis química , Chalcona/farmacología , Bases de Datos Factuales , Evaluación Preclínica de Medicamentos , Humanos , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Modelos Moleculares , Receptores de Leucotrienos/metabolismoRESUMEN
A gamma-carboline series of cysLT(1) receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.
Asunto(s)
Carbolinas/química , Química Farmacéutica/métodos , Antagonistas de Leucotrieno/síntesis química , Receptores de Leucotrienos/química , Administración Oral , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Diseño de Fármacos , Cobayas , Humanos , Concentración 50 Inhibidora , Antagonistas de Leucotrieno/farmacología , Modelos Químicos , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.
Asunto(s)
Amidas/síntesis química , Alcanfor/análogos & derivados , Compuestos Epoxi/química , Propionatos/química , Compuestos de Sulfonio/química , Alcanfor/química , Cristalografía por Rayos X , Ácidos Dicarboxílicos/síntesis química , Antagonistas de Leucotrieno/síntesis química , Conformación Molecular , Estereoisomerismo , Sulfuros/síntesis química , TermodinámicaRESUMEN
The syntheses of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl) prop-2-enoic acid (VUFB 20609) and racemic 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy) phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as new potential antileukotrienic drugs are described. Due to a low reactivity of the 4-substituted aryl bromides (coupling of the 4-substituted aryl bromides do not provide an activating functional group with 4-methoxybenzene-1-thiol), special conditions, in particular specific heterogeneous copper catalysts, were used. Catalytic hydrogenation of the conjugated double bond on Pd/C in the presence of the sulfanyl group is discussed. In-vitro cytotoxicity testing was performed using a microplate colorimetric acid phosphatase assay. Antiplatelet activity was evaluated using an in-vitro test in human platelet-rich plasma. Some substances inhibited arachidonic acid-induced platelet aggregation.
Asunto(s)
Antagonistas de Leucotrieno/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Quinolinas/síntesis química , Sulfuros/síntesis química , Ácido Araquidónico/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Hidrogenación , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Estructura Molecular , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Quinolinas/química , Quinolinas/farmacología , Estereoisomerismo , Sulfuros/química , Sulfuros/farmacologíaRESUMEN
The reaction of an amide-stabilized sulfonium ylide bearing chiral groups on sulfur has been investigated. We have discovered that the camphor-derived amide-stabilized ylide reacts with aldehydes at -50 degrees C in ethanol to give glycidic amides in one step with up to 99% ee and complete diastereoselectivity. From analyzing reactions of different ratios of diastereomers at sulfur it was found that the major diastereomer gave very high enantioselectivity, while the minor one gave much lower selectivity (54% ee). Further mechanistic studies have revealed that enantioselectivity is controlled not in the betaine-forming step (C-C bond formation is reversible) but in the different barriers to bond rotation around the newly formed C-C of the two diastereomeric betaines. Further transformations of epoxyamides were investigated. It was found that epoxyamides could be converted into epoxyketones by reaction with organolithium reagents and that they could be ring-opened by nucleophiles with complete regioselectivity using Yb(OTf)3. The practicality of the process has been exemplified in the synthesis of SK&F 104353, a leukotriene D4 antagonist in the potential treatment of bronchial asthma.
Asunto(s)
Amidas/química , Alcanfor/análogos & derivados , Compuestos Epoxi/química , Propionatos/química , Compuestos de Sulfonio/química , Amidas/síntesis química , Alcanfor/química , Ácidos Dicarboxílicos/síntesis química , Compuestos Epoxi/síntesis química , Antagonistas de Leucotrieno/síntesis química , Propionatos/síntesis química , EstereoisomerismoRESUMEN
Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4, 4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47.Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47.Na inhibited ionophore-stimulated LTB(4) formation with an IC(50) = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC(4) and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC(4) (IC(50) = 0.16 nM) over PGE(2) (IC(50) = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED(50) = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB(4), ED(50) = 2.5 mg/kg; LTE(4), ED(50) = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED(50) = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB(4) and LTC(4) but not PGH(2) biosynthesis. However, 47.Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47.Na acts as a FLAP inhibitor.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Antagonistas de Leucotrieno/síntesis química , Ácidos Pentanoicos/síntesis química , Quinolinas/síntesis química , Administración Oral , Anafilaxia/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/citología , Broncoconstricción/efectos de los fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacología , Evaluación Preclínica de Medicamentos , Eosinófilos/patología , Cobayas , Humanos , Técnicas In Vitro , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacocinética , Antagonistas de Leucotrieno/farmacología , Leucotrieno B4/antagonistas & inhibidores , Leucotrieno B4/biosíntesis , Pulmón/patología , Macaca fascicularis , Ratones , Neutrófilos/metabolismo , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Peritoneo/metabolismo , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A combinatorial mini library of naphthalene substituted chalcones has been prepared by solution phase chemistry. Screening of these mixtures for leukotriene B4 inhibitory activity using human whole blood assay (HWBL) afforded a lead compound, 1-(6-butoxy-2-naphthyl)-3-(4-nitrophenyl)-prop-2-en-1-one (K4A3) with an IC50 value of 18.5 microM.
Asunto(s)
Antagonistas de Leucotrieno/síntesis química , Leucotrieno B4/antagonistas & inhibidores , Chalcona/química , Evaluación Preclínica de Medicamentos , Humanos , Antagonistas de Leucotrieno/farmacología , Leucotrieno B4/metabolismo , Naftalenos/químicaRESUMEN
The two geminal ethyl groups in the succinic acid moiety of CGP57698 (4-[3-(7-fluoro-2-quinolinyl-methoxy)phenyl-amino]-2,2-diethyl-4-oxo- butanoic acid) are responsible for the high in vitro and in vivo potency of this peptidoleukotriene antagonist of the quinoline type. The synthesis and structure activity relationships of CGP57698 and its analogs are described.
Asunto(s)
Antagonistas de Leucotrieno/síntesis química , Leucotrieno D4/antagonistas & inhibidores , Quinolinas/química , Quinolinas/síntesis química , Animales , Antiasmáticos/síntesis química , Antiasmáticos/química , Antiasmáticos/farmacología , Disponibilidad Biológica , Broncoconstricción/efectos de los fármacos , Callithrix , Cobayas , Indicadores y Reactivos , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Leucotrieno E4/antagonistas & inhibidores , Conformación Molecular , Estructura Molecular , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Exploration of the indole nitrogen region of Zafirlukast (1) has uncovered a potent series of cysteinyl leukotriene D4 (LTD4) antagonists. These studies showed that a variety of functionality could be incorporated in this region of the molecule without sacrificing potency. Efforts to exploit this site in order to improve oral efficacy are discussed.