RESUMEN
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.
Asunto(s)
Isomerasas de Aminoácido/química , Antibacterianos/síntesis química , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/enzimología , Isomerasas de Aminoácido/antagonistas & inhibidores , Animales , Antibacterianos/farmacología , Disponibilidad Biológica , Diseño de Fármacos , Concentración 50 Inhibidora , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Profármacos , Unión Proteica , Sulfóxidos/química , Factores de TiempoRESUMEN
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.