title: Pyridodiazepine amines are selective therapeutic agents for helicobacter pylori by suppressing growth through inhibition of glutamate racemase but are predicted to require continuous elevated levels in plasma to achieve clinical efficacy.
abstract: A pyridodiazepine amine inhibitor of Helicobacter pylori glutamate racemase (MurI) was characterized. The compound was selectively active against H. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed against H. pylori if once-a-day dosing is required.
authors: Infection Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA boudewijn.dejonge@astrazeneca.com.
authors: Boudewijn L M
authors: BL
authors: de Jonge
authors: Infection Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Amy
authors: A
authors: Kutschke
authors: Infection Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Joseph V
authors: JV
authors: Newman
authors: Infection DMPK, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Michael T
authors: MT
authors: Rooney
authors: Infection Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Wei
authors: W
authors: Yang
authors: Cardiovascular Gastrointestinal Innovative Medicines Unit, AstraZeneca R&D Mölndal, Molndal, Sweden.
authors: Christer
authors: C
authors: Cederberg
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000658:Amoxicillin / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001381:Azepines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D001381:Azepines; D010457:Peptidoglycan; D011725:Pyridines; D000658:Amoxicillin; D000591:Amino Acid Isomerases; C062292:glutamate racemase
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