title: Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain.
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.
authors.affiliation: PanThera Biopharma, LLC, Aiea, HI 96701, USA.
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Jiao
authors.forename: Seongjin
authors.initials: S
authors.lastname: Kim
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.forename: April
authors.initials: A
authors.lastname: Thai
authors.forename: Lynne
authors.initials: L
authors.lastname: Cregar-Hernandez
authors.forename: Linda
authors.initials: L
authors.lastname: McKasson
authors.forename: Banumathi
authors.initials: B
authors.lastname: Sankaran
authors.forename: Axel
authors.initials: A
authors.lastname: Lehrer
authors.forename: Teri
authors.initials: T
authors.lastname: Wong
authors.forename: Lisa
authors.initials: L
authors.lastname: Johns
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Margosiak
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Alan T
authors.initials: AT
authors.lastname: Johnson
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000881:Anthrax / Q000188:drug therapy*; D000931:Antidotes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000187:drug effects* / Q000502:physiology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D011817:Rabbits; D051381:Rats
chemical_list: D000085:Acetates; D000931:Antidotes; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D065690:Cytochrome P-450 CYP2D6 Inhibitors; C030325:anthrax toxin; D019389:Cytochrome P-450 CYP2D6; C415326:phenoxyacetic acid