RESUMEN
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.
Asunto(s)
Amidas/química , Araquidonato 15-Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/química , Pirazoles/química , Amidas/síntesis química , Amidas/farmacología , Animales , Araquidonato 15-Lipooxigenasa/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Conejos , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
Asunto(s)
Imidazoles/farmacología , Inhibidores de la Lipooxigenasa , Inhibidores de la Lipooxigenasa/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Imidazoles/química , Inhibidores de la Lipooxigenasa/química , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de la Lipooxigenasa , Sulfonamidas/farmacología , Triptaminas/química , Animales , Inhibidores Enzimáticos/química , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of substituted spirobenzazepines was prepared and evaluated as V(1a) and V(2) dual vasopressin receptor antagonists. Compounds 7p and 7q have been shown to be not only potent inhibitors of vasopressin receptors, but also have exhibited an excellent overall pharmaceutical suitability profile.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/síntesis química , Animales , Benzazepinas/metabolismo , Benzazepinas/farmacología , Línea Celular , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ratas , Receptores de Vasopresinas/metabolismoRESUMEN
A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/farmacología , Compuestos de Espiro/farmacología , Benzazepinas/síntesis química , Línea Celular , AMP Cíclico/análisis , Humanos , Concentración 50 Inhibidora , Ligandos , Unión Proteica , Compuestos de Espiro/síntesis química , Relación Estructura-ActividadRESUMEN
A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.
Asunto(s)
Amidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Oxazinas/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Estabilidad de Medicamentos , Femenino , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Oxazinas/química , Oxazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
Asunto(s)
Proteínas de Transporte de Catión/antagonistas & inhibidores , Guanidinas/administración & dosificación , Imidazoles/administración & dosificación , Proteínas de la Membrana/antagonistas & inhibidores , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Proteínas de Transporte de Catión/metabolismo , Línea Celular , Guanidinas/química , Guanidinas/farmacocinética , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Proteínas de la Membrana/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Intercambiador 1 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , EstereoisomerismoRESUMEN
A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.