Pyridin-2-yl alkylamino substituted hydroxamic acid and uses thereof
Inventors
Jiao, Guan-Sheng • Kim, Seong Jin • Johnson, Alan T.
Assignees
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Publication Number
US-11299461-B2
Publication Date
2022-04-12
Expiration Date
Abstract
Compounds of formula I are provided: wherein X is NH, or CH2, Y is a single bond, or —CHR5—, R1 is H, C1-C4 alkyl, or C1-C4 hydroxyalkyl, R2 and R2′ are each independently H, C1-C4 alkyl, or C1-C4 hydroxyalkyl, each R3 is independently H, halo, —CF3, C1-C4 alkyl, or C1-C4 alkoxy, C3 perhaloalkyl, each R4 is independently H, halo, or C1-C4 alkyl, R5 is C1-C4 alkoxy, r is integer from 0 to 3; and p is integer from 0 to 3.
Core Innovation
The invention relates to hydroxamic acid compounds, including compounds 36–58, depicted with labeled stereochemical configuration and substituent variations. The compounds are presented as hydroxamic acids with defined structural features and different C-linked side chains, and the document includes LC/MS retention times, corresponding IR peak values, and analytical characterization.
The structural space of the invention is defined by a compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof. The formula specifies variable positions, including X is NH or CH2 and Y is either a single bond or —CHR5—, with R1, R2, R2′, each R3, each R4, and R5 constrained to defined classes, and indices r and p each from 0 to 3.
The document further includes assay context and potency data for inhibition of lethal factor (LF), using a FRET fluorescent peptide proteolytic assay and Ki tables. The biological context includes Bacillus anthracis, Bacillus anthracis toxin, and the Bacillus cereus group.
Claims Coverage
The claim coverage identifies three inventive features: a generic compound of formula I with constrained substituent classes and integer indices, a selection of specific depicted compounds with pharmaceutically acceptable salt, hydrate, or solvate forms, and a method of treating a subject exposed to Bacillus anthracis toxin using the claimed compound in a pharmaceutical composition.
Hydroxamic acid compound of formula I with constrained substituent classes
A compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is NH or CH2; Y is a single bond or —CHR5—; R1 is H, C1-C4 alkyl, or C1-C4 hydroxyalkyl; R2 and R2′ are each independently H, C1-C4 alkyl, or C1-C4 hydroxyalkyl; each R3 is independently H, halo, —CF3, C1-C4 alkyl, or C1-C4 alkoxy, C3 perhaloalkyl; each R4 is independently H, halo, or C1-C4 alkyl; R5 is C1-C4 alkoxy; r is integer from 0 to 3; and p is integer from 0 to 3.
Selected specific depicted compounds with salt, hydrate, or solvate forms
A compound selected from the specifically depicted set, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Therapeutically effective LF inhibition for subject exposure to Bacillus anthracis toxin
A method of treating a subject exposed to Bacillus anthracis toxin by administering a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 1.
Overall, the claims are focused on a hydroxamic acid scaffold defined by formula I with multiple constrained substituent variables and integer indices, selected depicted members with pharmaceutically acceptable salt, hydrate, or solvate variants, and treatment of Bacillus anthracis toxin exposure using the claimed compound in a pharmaceutical composition.
Stated Advantages
Treating and/or preventing symptoms of Bacillus anthracis infection via inhibition of Bacillus anthracis lethal factor (LF).
Documented Applications
Inhibition of lethal factor (LF) potency is documented using a LF FRET inhibitory assay with Ki (nM) tables across representative compound subclasses.
A method of treating a subject exposed to Bacillus anthracis toxin by administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I.
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