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Publication Number
US-11479576-B2
Publication Date
2022-10-25
Expiration Date
Abstract
The invention relates to a method of treating a mitochondrial DNA depletion syndrome, comprising administering to a patient a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to nucleic acid prodrug compounds and prodrugs of dNMPs for treating mitochondrial DNA depletion syndrome. The prodrugs include a nucleobase (NT) with variable substituents R1–R4 in formula (I) and related formula (Ia) embodiments, and preferred examples include Compounds 1017 and 15 as dNMP prodrugs.
The disclosure comprises administering to a patient a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat mitochondrial DNA depletion syndrome, specifically DGUOK deficiency. The compounds act as prodrugs of dNMPs and are activated via in vivo metabolism, including ester or carbonate hydrolysis.
The document also states calculated physicochemical properties, including logP, logS, and TPSA, and discusses possible stereochemical enrichment, including enantiomeric and diastereomeric enrichment. Example 3 reports that dNMP prodrugs, notably compounds 15 and 1017, rescue mtDNA depletion in patient-derived DGUOK-deficient fibroblasts in a dose-dependent manner, increasing mtDNA copy number.
Claims Coverage
The independent claim framework centers on administering a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat mitochondrial DNA depletion syndrome, specifically DGUOK deficiency. The claims define multiple inventive features through the structure of formula (I) and the nucleobase NT, with dependent claims narrowing NT to 9-adeninyl or 9-guaninyl and to corresponding prodrug moiety variants.
Treatment of DGUOK deficiency mitochondrial DNA depletion syndrome with formula (I) compounds
A method of treating a mitochondrial DNA depletion syndrome by administering a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the mitochondrial DNA depletion syndrome is DGUOK deficiency.
Constrained substituent definitions for formula (I) (R1–R4)
A compound of formula (I) wherein R1 is C5-14 aryl or mono-, bi-, or tricyclic heteroaryl; R2 and R2' each independently are hydrogen, alkyl or aralkyl; R3 is alkyl or aralkyl; and R4 is hydrogen or alkyl.
Nucleobase selection (NT) as the distinguishing structural feature
A compound of formula (I) wherein NT is a nucleobase.
Nucleobase narrowed to 9-adeninyl or 9-guaninyl
The method wherein NT is 9-adeninyl or 9-guaninyl.
Nucleobase extended to 9-adeninyl/9-guaninyl prodrug moiety variants
The method wherein NT is 9-adeninyl or 9-guaninyl or a 9-adeninyl or 9-guaninyl prodrug moiety.
Across the independent claim and dependent refinements, the inventive scope centers on using formula (I) prodrug compounds for treating mitochondrial DNA depletion syndrome caused by DGUOK deficiency, with defining constraints on R1–R4 substituents and a nucleobase (NT) that is further limited to 9-adeninyl/9-guaninyl and corresponding prodrug moiety variants.
Stated Advantages
Calculated physicochemical properties are provided for the compounds, including logP, logS, and TPSA.
The dNMP prodrugs, notably compounds 15 and 1017, rescue mtDNA depletion in patient-derived DGUOK-deficient fibroblasts.
The rescue effect is dose-dependent and increases mtDNA copy number.
Expected favorable physicochemical properties, including calculated logP, logS, and TPSA, to support cell membrane crossing and solubility in biological fluids.
Expected prodrug activation via in vivo metabolism, including ester or carbonate hydrolysis.
Documented Applications
Treatment of mitochondrial DNA depletion syndrome (MDS), specifically mitochondrial DNA depletion syndrome caused by DGUOK deficiency, by administering a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt.
Treatment of mitochondrial DNA depletion syndrome associated with DGUOK deficiency in a patient context by administering dNMP prodrugs, including compounds 15 and 1017.
Use of patient-derived DGUOK-deficient fibroblasts to demonstrate that dNMP prodrugs rescue mtDNA depletion with increased mtDNA copy number.
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