Oligomeric compounds and methods

1. An oligomeric compound comprising a single-stranded oligonucleotide consisting of 10-30 linked nucleosides, wherein the oligonucleotide comprises a phosphate stabilizing nucleoside at the 5′-end, wherein the phosphate stabilizing nucleoside comprises:

i) a 5′-terminal modified phosphate; or

ii) a 5′-terminal unmodified phosphate and a modified sugar moiety comprising a 5′ modification; and a linking group linking the phosphate stabilizing nucleoside to the remainder of the oligonucleotide; and wherein the remainder of the oligonucleotide comprises at least one region having a nucleoside motif:

(A) n -(B) n -(A) n -(B) n , wherein:

A and B are differently modified nucleosides; and

each n is independently selected from 1, 2, 3, 4, and 5; or

iii) both i) and ii).

2. The oligomeric compound of claim 1 , wherein:

the 5′-terminal modified phosphate is selected from: phosphonate, alkylphosphonate, substituted alkylphosphonate, aminoalkyl phosphonate, substituted aminoalkyl phosphonate, phosphorothioate, phosphoramidate, alkylphosphonothioate, substituted alkylphosphonothioate, phosphorodithioate, and thiophosphoramidate; and

the 5′-modification of the sugar moiety of the phosphate stabilizing nucleoside is selected from 5′-alkyl and 5′-halogen.

3. The oligomeric compound of claim 1 , wherein the modified phosphate is selected from: phosphonate, alkylphosphonate, and substituted alkylphosphonate.

4. The oligomeric compound of claim 1 , wherein A and B are each selected from: a 2′-F nucleoside, a 2′-OCH 3 nucleoside, a 2′-O(CH 2 ) 2 OCH 3 nucleoside, a (4′-CH 2 —O-2′) BNA nucleoside, a (4′-(CH 2 ) 2 —O-2′) BNA nucleoside, a (4′-CH(CH 3 )—O-2′) BNA nucleoside, a DNA nucleoside, an RNA nucleoside, and an F-HNA nucleoside.

5. The oligomeric compound of claim 1 , wherein at least one of A and B is a 2′-F, 2′-OCH 3 or 2′-O(CH 2 ) 2 OCH 3 nucleoside.

6. The oligomeric compound of claim 4 , wherein A is a 2′-F nucleoside and B is a 2′-OCH 3 nucleoside.

7. The oligomeric compound of claim 1 comprising a 3′-region consisting of from 1 to 5 nucleosides at the 3′-end of the oligomeric compound wherein:

the nucleosides of the 3′-region each comprises the same modification as one another; and

the nucleosides of the 3′-region are modified differently than the last nucleoside adjacent to the 3′-region.

8. The oligomeric compound of claim 7 , wherein the nucleosides of the 3′-region are 2′-O(CH 2 ) 2 OCH 3 nucleosides; and wherein the 3′-region consists of 2 linked nucleosides.

9. The oligomeric compound of claim 7 , wherein each nucleoside of the 3′-region comprises a thymine base.

10. The oligomeric compound of claim 1 , wherein the remainder of the oligonucleotide comprises at least one region of nucleosides having a motif I:

N f (PS)N m (PO), wherein:

N f is a 2′-F nucleoside,

N m is a 2′-OCH 3 nucleoside

PS is a phosphorothioate linking group; and

PO is a phosphodiester linking group.

11. The oligomeric compound of claim 10 comprising at least 2 regions of nucleosides having the motif I.

12. The oligomeric compound of claim 10 comprising at least 6 regions of nucleosides having the motif I.

13. The oligomeric compound of claim 10 comprising at least 7 regions of nucleosides having the motif I.

14. The oligomeric compound of claim 1 comprising one or more conjugate groups.

15. The oligomeric compound of claim 1 wherein the oligomeric compound is an RNAi compound.

16. A pharmaceutical composition comprising an oligomeric compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.

17. A method comprising contacting a cell with an oligomeric compound according to claim 1 .

18. The method of claim 17 , wherein the cell is in vitro.

19. The method of claim 17 , wherein the cell is in an animal.

20. The oligomeric compound of claim 1 , wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: halogen, allyl, amino, azido, thio, O-allyl, —O—C 1 -C 10 alkyl, —O—C 1 -C 10 substituted alkyl, —OCF 3 , —O—(CH 2 ) 2 —O—CH 3 , —O(CH 2 ) 2 SCH 3 , —O—(CH 2 ) 2 O—N(R m )(R n ), —O—CH 2 —C(═O)—N(R m )(R n ), where each R m and R n is, independently, H or substituted or unsubstituted C 1 -C 10 alkyl, —O[(CH 2 ) n O] m CH 3 , —O(CH 2 ) n NH 2 , —O(CH 2 ) n CH 3 , —O(CH 2 ) n ONH 2 , —OCH 2 C(═O)N(H)CH 3 , —O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , where n and m are from 1 to about 10; C 1 to C 10 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl.

21. The oligomeric compound of claim 1 , wherein the phosphate stabilizing nucleoside comprises a 5′ terminal modified phosphate and a modified sugar moiety comprising a 5′ modification.

22. The oligomeric compound of claim 21 , wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: halogen, allyl, amino, azido, thio, O-allyl, —O—C 1 -C 10 alkyl, —O—C 1 -C 10 substituted alkyl, —OCF 3 , —O—(CH 2 ) 2 —O—CH 3 , —O(CH 2 ) 2 SCH 3 , —O—(CH 2 ) 2 —O—N(R m )(R n ), —O—CH 2 —C(═O)—N(R m )(R n ), where each R m and R n is, independently, H or substituted or unsubstituted C 1 -C 10 alkyl, —O[(CH 2 ) n O] m CH 3 , —O(CH 2 ) n NH 2 , —O(CH 2 ) n CH 3 , —O(CH 2 ) n ONH 2 , —OCH 2 C(═O)N(H)CH 3 , —O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , where n and m are from 1 to about 10; C 1 to C 10 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl.

23. The oligomeric compound of claim 22 , wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: —F, —O—(CH 2 ) 2 —O—CH 3 , and —OCH 3 .