ABSTRACT
High-throughput screening uncovered a pyrazolopyrimidinedione hit as a selective, low micromolar inhibitor of Helicobacter pylori glutamate racemase (MurI). Variation of the substituents around the scaffold led to low nanomolar inhibitors and improved antibacterial activity. The challenge in this program was to translate excellent enzyme inhibition into potent antibacterial activity and pharmacokinetics suitable for oral therapy. Compounds were profiled for MurI inhibition, activity against H. pylori, microsomal stability, and pharmacokinetics in mice. Iterative cycles of analog synthesis and biological testing led to compounds with substituents optimized for both low MICs (2 microg/ml) and good microsomal stability. In order to achieve high bioavailability, a novel pro-drug approach was implemented wherein a solubilizing sulfoxide moiety is oxidized in vivo to a sulfone.
Subject(s)
Amino Acid Isomerases/chemistry , Anti-Bacterial Agents/chemical synthesis , Helicobacter Infections/drug therapy , Helicobacter pylori/enzymology , Amino Acid Isomerases/antagonists & inhibitors , Animals , Anti-Bacterial Agents/pharmacology , Biological Availability , Drug Design , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Models, Chemical , Prodrugs , Protein Binding , Sulfoxides/chemistry , Time FactorsABSTRACT
Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.
