The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection.
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.
Xiong
Yusheng
Y
Merck Research laboratories, Rahway, NJ 07065, USA. yusheng.xiong@merck.com
Wiltsie
Judyann
J
Woods
Andrea
A
Guo
Jian
J
Pivnichny
James V
JV
Tang
Wei
W
Bansal
Alka
A
Cummings
Richard T
RT
Cunningham
Barry R
BR
Friedlander
Arthur M
AM
Douglas
Cameron M
CM
Salowe
Scott P
SP
Zaller
Dennis M
DM
Scolnick
Edward M
EM
Schmatz
Dennis M
DM
Bartizal
Kenneth
K
Hermes
Jeffrey D
JD
MacCoss
Malcolm
M
Chapman
Kevin T
KT
D000818:Animals; D000881:Anthrax / Q000188:drug therapy / Q000517:prevention & control; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D008253:Macaca mulatta; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D051379:Mice; D015394:Molecular Structure; D011714:Pyrans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C509748:(2R)-2-((4-fluoro-3-methylphenyl)sulfonylamino)-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011714:Pyrans; C030325:anthrax toxin; D045726:Metalloproteases