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US 12,065,458 B2Granted
Trialkyne linking agents and methods of use
AssigneeArrowhead Pharmaceuticals, Inc.
InventorsZhen Li, Erich Altenhofer, Jeffrey Carlson, Matthew Fowler-Watters, Bo Chen
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Abstract
Described are improved linking agents that are useful for facilitating the attachment of targeting groups, pharmacokinetic (PK) enhancers or modifiers, or other delivery agents to oligonucleotides. The described linking agents may exhibit improved reaction yields, stability, and biological activity, particularly when used in connection with oligonucleotide-based compounds, such as RNA interference (RNAi) agents.
Claims19
A compound of Formula III,
- or a pharmaceutically acceptable salt thereof,
- wherein,
- L1, L2, and L3 are each linkers of the formula:
- L4 is selected from the group consisting of:
- wherein indicates the point of attachment;
- R4 is H or optionally substituted alkyl;
- X is O or S;
- and
- RNA comprises or consists of an RNAi agent.
6 more elements
A method of reacting a compound of Formula III
- with a targeting ligand (TL) comprising an azide to form a compound of Formula V
- wherein,
- L1, L2, and L3 are each linkers of the formula:
- L4 is selected from the group consisting of:
- wherein indicates the point of attachment;
- R4 is H or optionally substituted alkyl;
- TL is a targeting ligand;
- X is O or S;
- Y is O or S;
- and
- RNA comprises or consists of an RNAi agent.
8 more elements
A method of reacting a compound of Formula II:
- with an RNAi agent to form a compound of Formula III:
- wherein,
- L1, L2, and L3 are each linkers of the formula of the formula:
- L4 is selected from the group consisting of:
- wherein indicates the point of attachment;
- each instance of R1 is optionally substituted alkyl;
- R2 is optionally substituted alkyl;
- and
- R4 is H or optionally substituted alkyl
- X is O or S;
- and
- RNA comprises or consists of an RNAi agent.
9 more elements
Dependencies are inferred from the claim text.