RESUMEN
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.
Asunto(s)
Fibrinolíticos/síntesis química , Compuestos de Fenilurea/síntesis química , Antagonistas del Receptor Purinérgico P2Y/síntesis química , Piridinas/síntesis química , Urea/análogos & derivados , Animales , Arteriopatías Oclusivas/sangre , Arteriopatías Oclusivas/tratamiento farmacológico , Tiempo de Sangría , Fibrinolíticos/química , Fibrinolíticos/farmacología , Células HEK293 , Humanos , Masculino , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Agregación Plaquetaria/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Trombosis/sangre , Trombosis/tratamiento farmacológico , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.
Asunto(s)
Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Benzoxazoles/química , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of 2-hydroxy-N-arylbenzenesulfonamides were identified to be ATP-citrate lyase (ACL) inhibitors with compound 9 displaying potent in vitro activity (IC(50)=0.13 microM). Chronic oral dosing of compound 9 in high-fat fed mice lowered plasma cholesterol, triglyceride, and glucose, as well as inhibited weight gain.
Asunto(s)
ATP Citrato (pro-S)-Liasa/antagonistas & inhibidores , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Benceno/química , Sulfonamidas/química , Sulfonamidas/farmacología , Tejido Adiposo/efectos de los fármacos , Animales , Fármacos Antiobesidad/síntesis química , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Células Cultivadas , Colesterol/sangre , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Triglicéridos/sangreRESUMEN
It is well established that melanocortins are peptides that have potent anti-inflammatory activity. Recent research has focused on understanding which of the known melanocortin receptors mediates the anti-inflammatory actions of the melanocortins. The aim of this study was to assess the anti-inflammatory activity of a synthetic MC-1R agonist. BMS-470539 is a potent, selective, full agonist of human and murine MC-1R with EC(50) values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS-470539 dose-dependently inhibited TNF-alpha-induced activation of a NF-kappaB transcriptional reporter in human melanoma cells, which endogenously express MC-1R. In vivo studies with BMS-470539 demonstrated that subcutaneous administration of BMS-470539 resulted in a dose-dependent inhibition of LPS-induced TNF-alpha production in BALB/c mice. In this model, the compound had an ED(50) of approximately 10 micromol/kg and a pharmacodynamic half-life of approximately 8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t(1/2) of 1.7 h. In a model of lung inflammation, administration of 15 micromol/kg BMS-470539 resulted in a 45% reduction in LPS-induced leukocyte infiltration (an infiltrate comprised primarily of neutrophils). The compound was also effective in a model of delayed-type hypersensitivity, reducing paw swelling by 59%, comparable with that seen with 5 mg/kg dexamethasone. These studies demonstrate that a selective small molecule agonist of the melanocortin-1 receptor is a potent anti-inflammatory agent in vivo and provides compelling evidence for the involvement of this receptor in the modulation of inflammation.
Asunto(s)
Citocinas/metabolismo , Imidazoles/administración & dosificación , Leucocitos/efectos de los fármacos , Lipopolisacáridos/antagonistas & inhibidores , Receptor de Melanocortina Tipo 1/agonistas , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/química , Inflamación/inmunología , Leucocitos/inmunología , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Peso Molecular , Relación Estructura-Actividad , Factores de TiempoRESUMEN
beta-Alanine derivative 2 (IC(50)=16 nM) and related compounds were found to be potent MC4R agonists.
Asunto(s)
Dipéptidos/síntesis química , Dipéptidos/farmacología , Receptor de Melanocortina Tipo 4/agonistas , beta-Alanina/farmacología , Animales , Sitios de Unión , Dipéptidos/química , Dipéptidos/farmacocinética , Diseño de Fármacos , Conducta Alimentaria/efectos de los fármacos , Humanos , Cinética , Modelos Animales , Modelos Moleculares , Relación Estructura-Actividad , beta-Alanina/farmacocinéticaRESUMEN
The melanocortin-1 receptor (MC-1R) is a G-protein-coupled receptor involved in inflammation and skin pigmentation. Compound 2 is the first highly potent and selective MC-1R small-molecule agonist reported. Compound 2 showed efficacy in an acute model of inflammation, which has demonstrated the role of MC-1R in modulation of inflammation.