RESUMEN
A novel series of oxoindolin-3-ylidene ethyl benzohydrazides were designed, synthesized, and identified as small molecule agonists of thrombopoietin (TPO) receptor c-mpl. Sulfur-oxygen exchange in oxoindolin-3-ylidene ethyl benzohydrazides was found to improve their agonistic activities. Several oxoindolin-3-ylidene ethyl benzothiohydrazides have been identified as full agonists of c-mpl.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Imitación Molecular , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Péptidos/química , Receptores de Trombopoyetina/agonistasRESUMEN
Synthesis and evaluation of novel series of indoline-1- or 3,4-dihydroquinoline-1(2H)-substituted carbothiohydrazide or carbohydrazide based small molecule compounds as thrombopoietin (TPO) receptor agonists are reported. Members of these compounds have been identified as full agonists of human c-mpl in BaF3/TPOR cell line. Indoline-1-carbohydrazide 9b exhibited reasonable pharmacokinetic profile.
Asunto(s)
Hidrazinas/química , Indoles/química , Quinolinas/química , Receptores de Trombopoyetina/agonistas , Animales , Línea Celular , Humanos , Hidrazinas/síntesis química , Hidrazinas/farmacocinética , Indoles/síntesis química , Indoles/farmacocinética , Ratas , Receptores de Trombopoyetina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel pyrrolopyridazine derivatives have been discovered to be HER-2 inhibitors. These compounds selectively inhibited HER-2 kinase activity at low nanomolar concentrations. Compound 7d was identified as a potent HER-2 inhibitor with an IC(50) of 4 nM.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Piridazinas/farmacología , Pirroles/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Modelos Moleculares , Piridazinas/síntesis química , Pirroles/síntesis química , Relación Estructura-Actividad , TYK2 Quinasa/metabolismoRESUMEN
A series of novel C-12' substituted vinflunine derivatives have been synthesized. Several compounds in this series possess comparable in vitro cytotoxic potency against A549 cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Química Farmacéutica/métodos , Ensayos de Selección de Medicamentos Antitumorales , Vinblastina/análogos & derivados , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Microtúbulos/química , Modelos Químicos , Conformación Molecular , Azida Sódica/farmacología , Tubulina (Proteína)/química , Vinblastina/síntesis química , Vinblastina/química , Vinblastina/farmacologíaRESUMEN
Full details of three approaches to an entirely regio- and stereoselective synthesis of the well-known target reserpine are described, culminating in a total synthesis which efficiently meets these requirements.