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

Bioorganic & Medicinal Chemistry Letters
Guan-Sheng JiaoAlan T Johnson

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.

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Citations

Jun 19, 2013·Antimicrobial Agents and Chemotherapy·Mahtab MoayeriStephen H Leppla
Jan 23, 2014·Expert Opinion on Drug Discovery·Ekaterina M Nestorovich, Sergey M Bezrukov
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Feb 25, 2017·Chemical Reviews·Megan GarlandMatthew Bogyo

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