RNAi agents modified at the 4′-C position
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsMuthiah Manoharan, Shigeo Matsuda, Kallanthottathil G. Rajeev, Ivan Zlatev
Life of this patent
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Abstract
One aspect of the present invention relates to double-stranded RNAi (dsRNA) duplex agent capable of inhibiting the expression of a target gene in vivo. The dsRNA duplex comprises one or more 4′-modifications in one or both strand. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for in vivo therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.
Claims18
A double-stranded RNAi agent capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 12 to 30 nucleotides, wherein the duplex comprises at least one 4′-modified moiety, represented by one of the following formulas in group i) or group ii):
- wherein:
- R is independently H;
- OMe;
- F;
- OH;
- O-(CH2)2OMe;
- SMe, NMe2;
- NH2;
- Me;
- O-nPr;
- O-CH2C(O)NHMe;
- O-(CH2)2NMe2;
- O-(CH2)2O-(CH2)2 NMe2;
- O-alkyl;
- or O-alkylamino;
- R′ is independently H or Me;
- B is independently A;
- C;
- 5-Me-C;
- G;
- I;
- U;
- T;
- Y;
- 2-thiouridine;
- 4-thiouridine;
- C5-modified pyrimidines;
- C2-modified purines;
- N8-modified purines;
- phenoxazine;
- G-clamp;
- or non-canonical mono, bi and tricyclic heterocycles,
- Y and Y′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH2, CH2NH or CH2O, O, S, S(O), SO2, N(RN), C(R′)═C(R″), C≡C or C(O), NHCH(R)C(O), —C(O)—CH(R)—NH—, CO, CH═N—O,
- or heterocyclyl;
- and
- n is independently an integer from 0 to 14;
- L represents, in each occurrence, a ligand selected from the group consisting of a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide, peptide, oligopeptide, RGD peptide, peptidoid, folate, cholesterol, lipid, and heterocycle;
- and
- wherein the stereochemistry is R or S and combinations of R and S for the unspecified chiral centers;
- or
- wherein:
- R is independently H;
- OMe;
- OEt, F;
- OTBDMS;
- O-(CH2)2OMe;
- SMe, NMe2;
- NPhth;
- Me;
- O-nPr;
- O-alkyl;
- or O-alkylamino;
- R′ is independently H or Me;
- and
- Bp and B are each independently ABz;
- CAc;
- 5-Me-CBz;
- G;
- I;
- U;
- T;
- Y;
- 2-thiouridine;
- 4-thiouridine;
- C5-modified pyrimidines;
- C2-modified purines;
- N8-modified purines;
- phenoxazine;
- G-clamp;
- or non-canonical mono, bi and tricyclic heterocycles,
- wherein the stereochemistry is R or S and combinations of R and S for the unspecified chiral centers.
Dependencies are inferred from the claim text.