RESUMEN
We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes. Consequently, this position was used to introduce a variety of substituents to improve the physicochemical properties. Some of the resulting analogues were found to be superior to 7 both in terms of potency in vitro and aqueous solubility, which translated into significantly improved efficacy in the animal model after intravenous and oral administration. The best compound, 73, potently inhibited oxytocin-induced uterine contractions in nonpregnant rats and reduced spontaneous uterine contractions in late-term pregnant rats.
Asunto(s)
Hidrazinas/síntesis química , Receptores de Oxitocina/antagonistas & inhibidores , Sulfonamidas/síntesis química , Administración Oral , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Unión Competitiva , Línea Celular , Cricetinae , Cricetulus , Femenino , Humanos , Hidrazinas/química , Hidrazinas/farmacología , Técnicas In Vitro , Trabajo de Parto Prematuro/fisiopatología , Trabajo de Parto Prematuro/prevención & control , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Contracción Uterina/efectos de los fármacosRESUMEN
The widespread use of HTS and combinatorial chemistry techniques has led to the generation of large amounts of pharmacological data, which, in turn, has catalyzed the development of computational methods designed to reduce the time and cost in identifying molecules suitable for pharmaceutical development. This review focuses on the use of substructure-based in silico techniques for lead discovery, an effective and increasingly popular approach for augmenting the chance of selecting drug-like compounds for preclinical and clinical development.
Asunto(s)
Química Farmacéutica , Técnicas Químicas Combinatorias , Diseño de Fármacos , Modelos Químicos , Conformación Molecular , Preparaciones Farmacéuticas , Bases de Datos Factuales , Relación Estructura-ActividadRESUMEN
Cheminformatics is playing an ever-increasing role in small molecule drug discovery. The widespread use of high-throughput screening (HTS) and combinatorial chemistry techniques has led to the generation of large amounts of pharmacological data which, in turn, has catalyzed the development of computational methods designed to reduce the time and cost in identifying molecules suitable for pharmaceutical development. This review focuses on recent advances in the field of substructure analysis, an increasingly popular data mining technique with applications at many levels of the discovery process, including HTS, compound library design, virtual screening and the prediction of biological activity.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Animales , Técnicas Químicas Combinatorias/tendencias , Biología Computacional/métodos , Biología Computacional/tendencias , Predicción , Humanos , Relación Estructura-ActividadRESUMEN
Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure--activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme. Accordingly, we investigated the JNK-inhibiting properties of a number of variants of the right-hand moiety of the molecule, which led to the identification of 2-(benzoylaminomethyl)thiophene sulfonamide benzotriazole (AS600292, compound 50a), the first potent and selective JNK inhibitor of this class which demonstrates a protective action against neuronal cell death induced by growth factor and serum deprivation.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Sulfonamidas/síntesis química , Tiofenos/síntesis química , Animales , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Tiofenos/farmacologíaRESUMEN
Ischemic injuries are associated with several pathological conditions, including stroke and myocardial infarction. Several studies have indicated extensive apoptotic cell death in the infarcted area as well as in the penumbra region of the infarcted tissue. Studies with transgenic animals suggest that the mitochondrion-mediated apoptosis pathway is involved in ischemia-related cell death. This pathway is triggered by activation of pro-apoptotic Bcl-2 family members such as Bax. Here, we have identified and synthesized two low molecular weight compounds that block Bax channel activity. The Bax channel inhibitors prevented cytochrome c release from mitochondria, inhibited the decrease in the mitochondrial membrane potential, and protected cells against apoptosis. The Bax channel inhibitors did not affect the conformational activation of Bax or its translocation and insertion into the mitochondrial membrane in cells undergoing apoptosis. Furthermore, the compounds protected neurons in an animal model of global brain ischemia. The protective effect in the animal model correlated with decreased cytochrome c release in the infarcted area. This is the first demonstration that Bax channel activity is required in apoptosis.