RESUMO
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.
Assuntos
Descoberta de Drogas , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptores Adrenérgicos beta/metabolismo , Meia-Vida , Humanos , Ligação de Hidrogênio , Ligantes , Modelos MolecularesRESUMO
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.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/química , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/síntese química , Linhagem Celular , Sobrevivência Celular , Desenho de Fármacos , Humanos , Ligação Proteica , Pirimidinas/síntese químicaRESUMO
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.
Assuntos
Benzotiazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Benzotiazóis/metabolismo , Sítios de Ligação/fisiologia , Inibidores de Proteínas Quinases/metabolismoRESUMO
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.