RESUMEN
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Asunto(s)
Cicatriz/prevención & control , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Piel/efectos de los fármacos , Animales , Modelos Moleculares , Fosforilación , Ratas , Receptor Tipo I de Factor de Crecimiento Transformador betaRESUMEN
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Ésteres/metabolismo , Lactamas/farmacología , Sebo/efectos de los fármacos , Ceras/metabolismo , Administración Tópica , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Animales , Cricetinae , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ésteres/química , Lactamas/síntesis química , Lactamas/química , Modelos Animales , Modelos Moleculares , Estructura Molecular , Receptores Androgénicos/metabolismo , Sebo/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Ceras/químicaRESUMEN
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Cetonas/farmacología , Humanos , Modelos Moleculares , Monocitos/efectos de los fármacosRESUMEN
Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.
Asunto(s)
Amidas/química , Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Ácido Succínico/química , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Semivida , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.
Asunto(s)
Antagonistas de Andrógenos/química , Antagonistas de Receptores Androgénicos , Nitrilos/síntesis química , Nitrilos/farmacología , Sebo/efectos de los fármacos , Sebo/metabolismo , Antagonistas de Andrógenos/farmacología , Animales , Línea Celular , Cricetinae , Humanos , Insectos , Masculino , Mesocricetus , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores Androgénicos/metabolismoRESUMEN
A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model.
Asunto(s)
Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/química , Antagonistas de Receptores Androgénicos , Éteres Fenílicos/administración & dosificación , Éteres Fenílicos/síntesis química , Sebo/efectos de los fármacos , Sebo/metabolismo , Administración Tópica , Animales , Línea Celular Tumoral , Cricetinae , Humanos , Masculino , Mesocricetus , Receptores Androgénicos/química , Reproducibilidad de los ResultadosRESUMEN
A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.
Asunto(s)
Antagonistas de Receptores Androgénicos , Diseño de Fármacos , Folículo Piloso , Nitrilos/administración & dosificación , Nitrilos/farmacología , Sebo/efectos de los fármacos , Sebo/metabolismo , Administración Tópica , Animales , Fenómenos Químicos , Cricetinae , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Masculino , Mesocricetus , Nitrilos/metabolismo , Nitrilos/farmacocinéticaRESUMEN
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Asunto(s)
Antagonistas de Receptores Androgénicos , Flúor/química , Nitrilos/química , Nitrilos/farmacología , Receptores Androgénicos/metabolismo , Sebo/efectos de los fármacos , Sebo/metabolismo , Humanos , Concentración 50 Inhibidora , Metilación , Estructura Molecular , Nitrilos/síntesis química , Relación Estructura-ActividadRESUMEN
A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Asunto(s)
Aminopiridinas/química , Aminopiridinas/farmacología , Antagonistas de Receptores Androgénicos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Sebo/efectos de los fármacos , Sebo/metabolismo , Aminopiridinas/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C3H , Modelos Moleculares , Estructura Molecular , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Cabello/crecimiento & desarrollo , Hidrocarburos Fluorados/farmacología , Nitrilos/farmacología , Sebo , Animales , Cricetinae , Hidrocarburos Fluorados/farmacocinética , Masculino , Mesocricetus , Ratones , Modelos Moleculares , Nitrilos/farmacocinéticaRESUMEN
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/uso terapéutico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Sulfonamidas/síntesis química , Sulfonamidas/uso terapéutico , Transaminasas/antagonistas & inhibidores , Animales , Benzofuranos/química , Calcio/antagonistas & inhibidores , Calcio/metabolismo , Células Cultivadas , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Ácido Glutámico/efectos de los fármacos , Ácido Glutámico/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Estructura Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Asunto(s)
Inhibidores de Caspasas , Diseño de Fármacos , Serpinas/síntesis química , Serpinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Proteínas Virales , Sitios de Unión , Caspasa 1/metabolismo , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.