Abstract
Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, N.I.H., Intramural
MeSH terms
-
Acetates / chemical synthesis*
-
Acetates / pharmacokinetics
-
Acetates / pharmacology
-
Animals
-
Anthrax / drug therapy*
-
Antidotes / chemical synthesis*
-
Antidotes / pharmacokinetics
-
Antidotes / pharmacology
-
Antigens, Bacterial
-
Bacillus anthracis / drug effects*
-
Bacillus anthracis / physiology
-
Bacterial Toxins / antagonists & inhibitors*
-
Crystallography, X-Ray
-
Cytochrome P-450 CYP2D6 / metabolism
-
Cytochrome P-450 CYP2D6 Inhibitors
-
Microsomes, Liver / enzymology
-
Models, Molecular
-
Rabbits
-
Rats
Substances
-
Acetates
-
Antidotes
-
Antigens, Bacterial
-
Bacterial Toxins
-
Cytochrome P-450 CYP2D6 Inhibitors
-
anthrax toxin
-
Cytochrome P-450 CYP2D6
-
phenoxyacetic acid