ABSTRACT
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.
Subject(s)
Glucose Transporter Type 1/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Cell Line , Drug Discovery , Glucose Transporter Type 1/metabolism , Humans , Male , Pyrimidines/pharmacokinetics , Rats, Wistar , Structure-Activity RelationshipSubject(s)
Depsipeptides/chemistry , Depsipeptides/chemical synthesis , Cells, Cultured/drug effects , Cyclization , Depsipeptides/pharmacology , Enterococcus faecalis/drug effects , Enterococcus faecalis/growth & development , Lactams/chemistry , Models, Chemical , Peptides, Cyclic/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & developmentABSTRACT
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.