Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines.
An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface.
Geng
Bolin
B
AstraZeneca R&D Boston, Infection Discovery, 35 Gatehouse Drive, Waltham, MA 02451, USA. bolin.geng@astrazeneca.com
Basarab
Gregory
G
Comita-Prevoir
Janelle
J
Gowravaram
Madhusudhan
M
Hill
Pamela
P
Kiely
Andrew
A
Loch
James
J
MacPherson
Lawrence
L
Morningstar
Marshall
M
Mullen
George
G
Osimboni
Ekundayo
E
Satz
Alexander
A
Eyermann
Charles
C
Lundqvist
Tomas
T
D000588:Amines / Q000737:chemistry*; D000591:Amino Acid Isomerases / Q000737:chemistry*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019281:Dimerization; D015195:Drug Design; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000588:Amines; D000890:Anti-Infective Agents; D000591:Amino Acid Isomerases; C062292:glutamate racemase