RESUMEN
We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.
Asunto(s)
Descubrimiento de Drogas , Activadores de Enzimas/farmacología , Glucoquinasa/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activadores de Enzimas/síntesis química , Activadores de Enzimas/química , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Using a vHTS based on a pharmacophore alignment on known beta3-adrenoceptor ligands, a set of intriguing beta-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human beta2-AR antagonist.
Asunto(s)
Receptores Adrenérgicos beta/metabolismo , Semivida , Humanos , Enlace de Hidrógeno , Ligandos , Modelos MolecularesRESUMEN
Resulting from a vHTS based on a pharmacophore alignment on known ß3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ß3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hß1- and hß2-adrenoceptors and a promising safety profile.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 3/química , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/síntesis química , Línea Celular , Supervivencia Celular , Diseño de Fármacos , Humanos , Unión Proteica , Pirimidinas/síntesis químicaRESUMEN
Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC(50) values in the nanomolar range on different kinases down to 63nM.
Asunto(s)
Benzotiazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Benzotiazoles/metabolismo , Sitios de Unión/fisiología , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.