GalNAc compositions for improving siRNA bioavailability
Provided herein, are compositions comprising GaINAc moieties that may be conjugated to an oligonucleotide. The oligonucleotide may be a small interfering RNA or an antisense oligonucleotide. Also provided herein are methods of treatment that include administering the composition to a subject.
1. A compound represented by Formula (I) or (II):
or a salt thereof, wherein
J is an oligonucleotide;
each w is independently selected from any value from 1 to 20;
each v is independently selected from any value from 1 to 20;
n is selected from any value from 1 to 20;
m is selected from any value from 1 to 20;
z is selected from any value from 1 to 3, wherein
if z is 3, Y is C
if z is 2, Y is CR 6 , or
if z is 1, Y is C(R 6 ) 2 ;
Q is selected from:
C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —S(O)R 7 , and C 1-6 alkyl, wherein the C 1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 ;
R 1 is a linker selected from:
—O—, —S—, —N(R 7 )—, —C(O)—, —C(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )C(O)N(R 7 )—, —OC(O)N(R 7 )—, —N(R 7 )C(O)O—, —C(O)O—, —OC(O)—, —S(O)—, —S(O) 2 —, —OS(O) 2 —, —OP(O)(OR 7 )O—, —SP(O)(OR 7 )O—, —OP(S)(OR 7 )O—, —OP(O)(SR 7 )O—, —OP(O)(OR 7 )S—, —OP(O)(O)O—, —SP(O)(O—)O—, —OP(S)(O—)O—, —OP(O)(S—)O—, —OP(O)(O—)S—, —OP(O)(OR 7 )NR 7 —, —OP(O)(N(R 7 ) 2 )NR 7 —, —OP(OR 7 )O—, —OP(N(R 7 ) 2 )O—, —OP(OR 7 )N(R 7 )—, and —OPN(R 7 ) 2 NR 7 —;
each R 2 is independently selected from:
C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;
R 3 and R 4 are each independently selected from:
—OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;
each R 5 is independently selected from:
—OC(O)R 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)R 7 , —C(O)OR 7 , and —C(O)N(R 7 ) 2 ;
each R 6 is independently selected from:
hydrogen;
halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ; and
C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;
each R 7 is independently selected from:
hydrogen;
C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and
C 3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl.
2. The compound or salt of claim 1 , wherein each w, v, n and m is independently selected from any value from 1 to 5.
3. The compound or salt of claim 1 , wherein each w is 1, v is 1, n is 1 or 2, and m is 1 or 2.
4. The compound or salt claim 1 , wherein Q is selected from C 5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 .
5. The compound or salt of claim 1 , wherein R 1 is selected from —OP(O)(OR 7 )O—, —OP(S)(OR 7 )O—, —OP(O)(O—)O—, —OP(S)(O—)O—, —OP(O)(S—)O—, and —OP(OR 7 )O—.
6. The compound or salt of claim 1 , wherein R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from —OR 7 , —OC(O)R 7 , —SR 7 , and —N(R 7 ) 2 .
7. The compound or salt of claim 1 , wherein R 3 is selected from —OR 7 —SR 7 , —OC(O)R 7 , and —N(R 7 ) 2 .
8. The compound or salt of claim 1 , wherein R 4 is selected from —OR 7 —SR 7 , —OC(O)R 7 , and —N(R 7 ) 2 .
9. The compound or salt of claim 1 , wherein R 5 is selected from —OC(O)R 7 and —N(R 7 )C(O)R 7 .
10. The compound or salt of claim 1 , wherein each R 7 is independently selected from:
hydrogen; and
C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, or 3- to 10-membered heterocycle.
11. The compound of claim 1 , wherein the compound comprises:
12. The compound of claim 1 , wherein the oligonucleotide (J) is attached to R 1 at a 5′ end of the oligonucleotide.
13. The compound of claim 12 , wherein the 5′ end of the oligonucleotide comprises a phosphate.
14. The compound of claim 12 , wherein the 5′ end of the oligonucleotide comprises a phosphorothioate.
15. The compound of claim 1 , wherein the oligonucleotide comprises a phosphorothioate linkage.
16. The compound of claim 1 , wherein the oligonucleotide comprises a 2′ O-methyl or 2′ fluoro modified nucleoside.
17. The compound of claim 1 , wherein the oligonucleotide comprises a small interfering RNA (siRNA).
18. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier, excipient, or diluent.
19. A compound comprising:
wherein J comprises an oligonucleotide.
20. The compound of claim 19 , wherein the oligonucleotide comprises a siRNA.