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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
- 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.
- Subjects :
- Models, Molecular
Anthrax lethal factor endopeptidase
Antidotes
Bacterial Toxins
Clinical Biochemistry
Pharmaceutical Science
Acetates
Crystallography, X-Ray
medicine.disease_cause
Biochemistry
Article
Cytochrome P-450 CYP2D6 Inhibitors
Anthrax
Drug Discovery
medicine
Animals
Molecular Biology
ADME
Antigens, Bacterial
biology
Toxin
Chemistry
Organic Chemistry
biology.organism_classification
In vitro
Rats
Bacillus anthracis
Cytochrome P-450 CYP2D6
Toxicity
Microsomes, Liver
Microsome
Molecular Medicine
Rabbits
Subjects
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