CONJUGATES AND METHODS FOR TREATING ACROMEGALY
Provided herein are certain nucleic acids (e.g., double stranded siRNA molecules), as well as conjugates that comprise a targeting moiety, a double stranded siRNA, and optional linking groups. Certain embodiments also provide synthetic methods useful for preparing the conjugates. He conjugates are useful to treat certain diseases, such as acromegaly.
1 . A compound of formula (I):
wherein:
R 1 a is targeting ligand;
L 1 is absent or a linking group;
L 2 is absent or a linking group;
R 2 is a siRNA molecule selected from any one of siRNA 1-siRNA 28;
the ring A is absent, a 3-20 membered cycloalkyl, a 5-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocycloalkyl;
each R A is independently selected from the group consisting of hydrogen, hydroxy, CN, F, Cl, Br, I, —C 1-2 alkyl-OR B , C 1-10 alkyl C 2-10 alkenyl, and C 2-10 alkynyl; wherein the C 1-10 alkyl C 2-10 alkenyl, and C 2-10 alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, and C 1-3 alkoxy;
R B is hydrogen or a protecting group; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
or a salt thereof.
2 . The compound of claim 1 , wherein R 1 is —C(H) (3-p) (L 3 -saccharide) p ;
wherein each L 3 is independently a linking group;
p is 1, 2, or 3; and
saccharide is a monosaccharide or disaccharide
or a salt thereof.
3 . The compound of claim 2 , wherein the saccharide is:
wherein:
X is NR 3 , and Y is selected from —(C═O)R 4 , —SO 2 R 5 , and —(C═O)NR 6 R 7 ; or X is —(C═O)— and Y is NR 8 R 9 ;
R 3 is hydrogen or (C 1 -C 4 )alkyl;
R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )alkoxy and (C 3 -C 6 )cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 10 is —OH, —NR 8 R 9 or —F; and
R 11 is —OH, —NR 8 R 9 , —F or 5 membered heterocycle that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, carboxyl, amino, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy;
or a salt thereof.
4 . The compound of claim 2 or 3 , wherein the saccharide is selected from the group consisting of:
or a salt thereof.
5 . The compound of any one of claims 2 - 4 , wherein the saccharide is:
or a salt thereof.
6 . The compound of claim 1 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
7 . The compound of claim 1 , wherein the compound of formula (I) is:
or a pharmaceutically acceptable salt thereof, wherein the siRNA depicted is selected from any one of siRNA 1-siRNA 28.
8 . The compound of any one of claims 1 - 7 , wherein the siRNA is selected from any one of siRNA 1-siRNA 24.
9 . The compound of any one of claims 1 - 7 , wherein the siRNA is selected from any one of siRNA 25-siRNA 28.
10 . The compound of claim 9 , wherein the siRNA is siRNA 25.
11 . The compound of claim 9 , wherein the siRNA is siRNA 26.
12 . The compound of claim 9 , wherein the siRNA is siRNA 27.
13 . The compound of claim 9 , wherein the siRNA is siRNA 28.
14 . A method for treating acromegaly, comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 - 13 .
15 . A method for reducing insulin-like growth factor-1 (IGF-1) in a patient, comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 - 13 .
16 . A method for reducing growth hormone in a patient, comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 - 13 .
17 . A method for reducing growth hormone receptor (GHR) in the liver in a patient, comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 - 13 .
18 . The method of any one of claims 14 - 17 , wherein the compound of formula (I) is administered subcutaneously.
19 . A double stranded siRNA molecule selected from the group consisting of siRNA 1-siRNA 28.
20 . A composition comprising a double stranded siRNA molecule of claim 19 .