Synthesis and properties of 2-(naphthosultamyl)methyl-carbapenems with potent anti-MRSA activity: discovery of L-786,392.
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Ratcliffe
R W
RW
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA.
Wilkening
R R
RR
Wildonger
K J
KJ
Waddell
S T
ST
Santorelli
G M
GM
Parker
D L
DL
Morgan
J D
JD
Blizzard
T A
TA
Hammond
M L
ML
Heck
J V
JV
Huber
J
J
Kohler
J
J
Dorso
K L
KL
St Rose
E
E
Sundelof
J G
JG
May
W J
WJ
Hammond
G G
GG
D000818:Animals; D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004352:Drug Resistance, Microbial; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D015780:Carbapenems; D007769:Lactams; D013844:Thiazoles; C117024:L 786392