7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)
Inventors
Giroux, Simon • Clark, Michael Philip • Brodney, Michael Aaron • Jones, Peter • Deninno, Michael Paul • Gu, Wenxin • Tang, Qing • STONE, Steven David • Senter, Timothy J. • Gale-Day, Zachary • BOUCHER, Diane Marie • Fanning, Lev T.D. • HALL, Amy B. • Hurley, Dennis James • Johnson, JR., Mac Arthur • Maxwell, John Patrick • Swett, Rebecca Jane • TAPLEY, Timothy Lewis • Thomson, Stephen A. • Damagnez, Veronique • Cottrell, Kevin Michael
Assignees
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Publication Number
US-12662471-B2
Publication Date
2026-06-23
Expiration Date
Abstract
7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD).
Core Innovation
The patent discloses compounds of Formula I, including Formula Ia–Id scaffold variants, 7- or 8-hydroxy-isoquinoline derivatives, and 7- or 8-hydroxy-quinoline derivatives, alongside tautomers, deuterated derivatives, and pharmaceutically acceptable salts. The genus defines structural ring features and substituent alternatives, specifying R1 as —OH, R1′ as hydrogen or halogen, and W1 and W2 as —CH. Disclosed embodiments also encompass silicon-, boron-, and phosphorus-substituted derivatives bearing a hydroxy-substituted fused nitrogen-containing bicyclic aromatic scaffold.
The disclosed compounds, illustrated by compounds 1–361, function as alpha-1 antitrypsin modulators. Cell-based functional alpha-1 antitrypsin assays and biochemical Z-alpha-1 antitrypsin and elastase screening result data establish that multiple compounds demonstrate functional activity. The illustrated embodiments encompass carboxyalkyl, aryl-carboxylic-acid, ether, amide, nitrile, aminoalkyl, and azaspiro substituents. The specific technical problem being solved is not explicitly described in patent.
Claims Coverage
The claims identify two independent claims, defining two inventive features directed to chemical compound genera and selected derivatives.
Formula I compound genus and derivatives
Claim 1 covers a compound of Formula I, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof. The claim specifies ring features and substituent alternatives, including R1 as —OH, defined options for R1′, W1, W2, X, Y, and substituents R2 through R8, alongside conditions linking X, Y, and bond (z).
Selected compounds and derivatives
Claim 19 covers a compound selected from an enumerated list, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, wherein the specific compound structures in the list are not visible in the provided claim text.
The independent claims cover the defined Formula I compound genus and an enumerated group of selected compounds, together with deuterated derivatives and pharmaceutically acceptable salts.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of alpha-1 antitrypsin deficiency, including deficiency associated with Z, ZZ, and SZ genotypes or mutations.
Combination therapy with additional active agents, including plasma-derived or recombinant alpha-1 antitrypsin, for the treatment of alpha-1 antitrypsin deficiency.
Increasing or modulating alpha-1 antitrypsin activity in vivo, ex vivo, or in vitro by contacting alpha-1 antitrypsin with a claimed compound, deuterated derivative, or pharmaceutically acceptable salt.
Pharmaceutical compositions comprising a claimed compound, deuterated derivative, or pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier.
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