Side chain SAR of bicyclic beta-lactamase inhibitors (BLIs). 1. Discovery of a class C BLI for combination with imipinem.
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Blizzard
Timothy A
TA
Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA. tim_blizzard@merck.com
Chen
Helen
H
Kim
Seongkon
S
Wu
Jane
J
Young
Katherine
K
Park
Young-Whan
YW
Ogawa
Amy
A
Raghoobar
Susan
S
Painter
Ronald E
RE
Hairston
Nichelle
N
Lee
Sang Ho
SH
Misura
Andrew
A
Felcetto
Tom
T
Fitzgerald
Paula
P
Sharma
Nandini
N
Lu
Jun
J
Ha
Sookhee
S
Hickey
Emily
E
Hermes
Jeff
J
Hammond
Milton L
ML
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D015780:Carbapenems / Q000737:chemistry* / Q000494:pharmacology; D004338:Drug Combinations; D055808:Drug Discovery / Q000379:methods*; D015378:Imipenem / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000201:enzymology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance / Q000187:drug effects / Q000502:physiology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D015780:Carbapenems; D004338:Drug Combinations; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; D001618:beta-Lactamases