RÉSUMÉ
The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure-activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.
Sujet(s)
Transporteur de glucose de type 1/antagonistes et inhibiteurs , Pyrimidines/composition chimique , Pyrimidines/pharmacologie , Animaux , Lignée cellulaire , Découverte de médicament , Transporteur de glucose de type 1/métabolisme , Humains , Mâle , Pyrimidines/pharmacocinétique , Rat Wistar , Relation structure-activitéSujet(s)
Depsipeptides/composition chimique , Depsipeptides/synthèse chimique , Cellules cultivées/effets des médicaments et des substances chimiques , Cyclisation , Depsipeptides/pharmacologie , Enterococcus faecalis/effets des médicaments et des substances chimiques , Enterococcus faecalis/croissance et développement , Lactames/composition chimique , Modèles chimiques , Peptides cycliques/composition chimique , Staphylococcus aureus/effets des médicaments et des substances chimiques , Staphylococcus aureus/croissance et développement , Streptococcus pneumoniae/effets des médicaments et des substances chimiques , Streptococcus pneumoniae/croissance et développementRÉSUMÉ
Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.