Back to Search Start Over

Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain

Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain

Authors :
Lisa Johns
Seongjin Kim
Axel T. Lehrer
Alan T. Johnson
Stephen A. Margosiak
April Thai
Guan-Sheng Jiao
Banumathi Sankaran
Linda McKasson
Teri Wong
Devorah Crown
Stephen H. Leppla
Lynne Cregar-Hernandez
Mahtab Moayeri
Source :
Bioorganic & Medicinal Chemistry Letters. 22:2242-2246
Publication Year :
2012
Publisher :
Elsevier BV, 2012.

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.

Details

ISSN :
0960894X
Volume :
22
Database :
OpenAIRE
Journal :
Bioorganic & Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....0149d4f3b3b427a4f4c3e025e425da71
Full Text :
https://doi.org/10.1016/j.bmcl.2012.01.095