title: Design of Helicobacter pylori glutamate racemase inhibitors as selective antibacterial agents: a novel pro-drug approach to increase exposure.
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.
authors.affiliation: Cancer and Infection Research Area, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. greg.basarab@astrazeneca.com
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Basarab
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hill
authors.forename: Abdullah
authors.initials: A
authors.lastname: Rastagar
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Webborn
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D015195:Drug Design; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D011355:Prodrugs; D011485:Protein Binding; D013454:Sulfoxides / Q000737:chemistry; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D011355:Prodrugs; D013454:Sulfoxides; D000591:Amino Acid Isomerases; C062292:glutamate racemase