http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-112064-A1
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_137632ce410f947dc83f29aa9ca2618f http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_05a203d85ee01909eaf728dc16f0f6cb |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07H21-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07H21-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C12N15-113 |
| filingDate | 2018-06-01-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationDate | 2019-09-18-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | AR-112064-A1 |
| titleOfInvention | OLIGONUCLEOTHICAL COMPOSITIONS AND THEIR METHODS OF USE |
| abstract | Among other things, the present disclosure provides designed PNPLA3 oligonucleotides, their compositions, and methods. In some embodiments, the provided oligonucleotide compositions provide enhanced single-stranded RNA interference and / or RNase H-mediated disintegration. Among other things, the present disclosure encompasses the recognition that oligonucleotide structural elements, such as base sequence, chemical modifications (eg, sugar, base, and / or internucleotide linkages) or their patterns, conjugation to additional chemical moieties, and / or stereochemistry [eg, stereochemistry of chiral structural centers (chiral internucleotide linkages)], and / or their patterns, can have a significant impact on the properties and activities of the oligonucleotides, for example, RNA interference activity (RNAi), stability, delivery, etc. In some embodiments, the present disclosure provides methods for the treatment of disease using oligonucleotide compositions provided, for example, in RNA interference and / or RNase H-mediated disintegration. Claim 1: A compound having the formula ( 1): Y¹-L¹- (Z¹⁰) ᶻₐ (1) or a pharmaceutically acceptable salt of said compound, where Y¹ is an oligonucleotide that targets PNPLA3; za is 1, 2, or 3; and L¹ is a compound of the formula selected from the group of formulas (2), where the connection sites with Y¹ and Z¹⁰ are indicated, where each T¹ is independently absent or is alkylene, alkenylene or alkynylene, where one or several -CH₂- groups of the alkylene, alkenylene or alkynylene can each be replaced, independently, with a heteroatomic group independently selected from -O-, -S- and -N (R⁴⁹) -, where the groups heteroatomics are separated by at least 2 carbon atoms; each Q¹ is independently absent or is -C (O) -, -C (O) -NR⁴⁹-, -NR⁴⁹-C (O) -, -OC (O) -NR⁴⁹-, -NR⁴⁹-C (O) -O-, -CH₂-, -NR⁴⁹C (O) NR⁴⁹-, a bivalent heteroaryl group or a heteroatomic group selected from -O-, -S-, -SS-, -S (O) -, -S (O) ₂- and -NR⁴⁹-, where at least two carbon atoms separate the heteroatomic groups -O-, -S-, -SS-, -S (O) -, -S (O) ₂- and -NR⁴⁹- from any other heteroatomic group or a structure of formula (3), wherein R⁵³ is -O or -NH- and R⁵⁴ is -O or -S; each R⁴⁹ is independently -H, -C₁₋₂₀ alkyl or -C₃₋₆ cycloalkyl, wherein one to six -CH₂- alkyl or cycloalkyl groups separated by at least two carbon atoms can be replaced with -O -, -S- or -N (R⁴⁹ᵃ) - and -CH₃ of the alkyl can be replaced with a heteroatomic group selected from -N (R⁴⁹ᵃ) ₂, -OR⁴⁹ᵃ, and -S (R⁴⁹ᵃ), where the heteroatomic groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halogen atoms and wherein each R⁴⁹ᵃ is independently -H, -C₁₋₆alkyl or -C₃₋₆cycloalkyl; R⁵³ is -O or -NH; R⁵⁴ is -O or -S; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40; where if n is greater than 0, each T¹ and each Q¹ of each (T¹-Q¹-T¹-Q¹) is selected independently; and each Z¹⁰ is, independently, a compound of the formula selected from the group of formulas (4) or one of its geometric or positional isomers, where the connection site with L¹ is indicated, where each R⁴⁶ is, from independent mode, -CN, -CH₂-CN, -CºCH, -CH₂-N₃, -CH₂-NH₂, -CH₂-N (R⁵²) -S (O) ₂-R⁵¹, -CH₂-CO₂H, -CO₂H, -CH₂ -OH, -CH₂-SH, -CH = CH-R⁵¹, -CH₂-R⁵¹, CH₂-S-R⁵¹, CH₂-N (R⁵²) -R⁵¹, -CH₂-N (R⁵²) -C (O) -R⁵¹, -CH₂-N (R⁵²) -C (O) -O-R⁵¹, -CH₂-N (R⁵²) -C (O) -N (R⁵²) -R⁵¹, -CH₂-O-R⁵¹, -CH₂-OC (O ) -R⁵¹, -CH₂-OC (O) -N (R⁵²) -R⁵¹, CH₂-OC (O) -O-R⁵¹, -CH₂-S (O) -R⁵¹, -CH₂-S (O) ₂-R⁵¹ , -CH₂-S (O) ₂-N (R⁵²) -R⁵¹, -C (O) -NH₂, -C (O) -O-R⁵¹, -C (O) -N (R⁵²) -R⁵¹ or aryl or heteroaryl, where aryl or heteroaryl is optionally substituted with R⁵¹; each R⁴⁷ is, independently, -OH, -N₃, -N (R⁴⁸) ₂, -N (R⁴⁸) -C (O) -R⁴⁸, -N (R⁴⁸) -C (O) -N (R⁴⁸) ₂ -, -N (R⁴⁸) -C (O) -OR⁴⁸, -N (R⁴⁸) -S (O) ₂-R⁴⁸, tetrazole or triazole, wherein the tetrazole and triazole are optionally substituted with R⁴⁸; each R⁴⁸ is independently -H, -C₁₋₅alkyl, halo-substituted C₁₋₅ alkyl, -halosubstituted -C₃₋₆cycloalkyl, -C₁₋₅alkenyl, -C₁₋₅alkynyl, -halosubstituted C₁₋₅alkenyl, - Halosubstituted C₁₋₅ alkynyl or -C₃₋₆ cycloalkyl, wherein a -CH₂- group of the alkyl or cycloalkyl can each be replaced, independently, with a heteroatomic group selected from -O-, -S- and -N ( R⁵²) - and -CH₃ of the alkyl may each be replaced, independently, with a heteroatomic group selected from -N (R⁵²) ₂, -OR⁵² and -S (R⁵²), wherein the heteroatomic groups are separated by at least 2 carbon atoms; each R⁵¹ is independently -H, -C₃₋₂₀ cycloalkyl, -C₁₋₆₀ alkenyl, -C₁₋₆₀ alkynyl, or -Calalkyl, wherein one to six -CH₂- groups of the cycloalkyl or 1 to 20 -CH₂- groups of the alkyl may each be replaced, independently, with heteroatoms independently selected from -O-, -S- and -N (R⁴⁹) -, where the heteroatoms are separated by at least two atoms of Carbon and -CH₃ of the alkyl can each be replaced, independently, with a heteroatomic group selected from -N (R⁴⁹) ₂, -OR⁴⁹, and -S (R⁴⁹), where the heteroatomic groups are separated by at least 2 atoms carbon and wherein alkyl, alkenyl, alkynyl, and cycloalkyl may be substituted with halogen atoms; and each R⁵² is independently -H, -C₁₋₂₀alkyl, -C₁₋₂₀alkenyl, -C₁₋₂₀alkynyl, or -C₃₋₆cycloalkyl, wherein one to six separate -CH₂- alkyl or cycloalkyl groups at least two carbon atoms may each be replaced, independently, with a heteroatom independently selected from -O-, -S- or -N (R⁴⁹) - and -CH₃ of the alkyl may each be replaced, independently, with a heteroatomic group selected from -N (R⁴⁹) ₂, -OR⁴⁹ and -S (R⁴⁹), wherein the heteroatomic groups are separated by at least 2 carbon atoms; and wherein the alkyl, alkenyl, alkynyl, and cycloalkyl may be substituted with halogen atoms. |
| priorityDate | 2017-06-02-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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Total number of triples: 22.