Ionizable cationic lipid for RNA delivery
Disclosed herein is a compound of Formula I, wherein R 1 is a branched chain alkyl consisting of 10 to 31 carbons; R 2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons, or a branched chain alkyl consisting of 10 to 31 carbons; L 1 and L 2 are the same or different, each a linear alkane of 1 to 20 carbons or a linear alkene of 2 to 20 carbons; X 1 is S or O; R 3 is a linear or branched alkylene consisting of 1 to 6 carbons; and R 4 and R 5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt or solvate thereof.
1. A compound of Formula I
wherein
R 1 is
R 2 is
L 1 and L 2 are each independently a linear C 1 -C 7 alkyl;
X 1 is S;
R 3 is a linear C 1 -C 6 alkyl; and
R 4 and R 5 are each independently a linear C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein L 2 is C 5 -C 7 alkyl.
3. The compound of claim 1 , wherein L 1 is C 3 -C 7 alkyl.
4. The compound of claim 1 , wherein R 3 is ethyl, propyl or butyl.
5. The compound of claim 1 , wherein R 4 and R 5 are each independently methyl or ethyl.
6. The compound of claim 1 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 3 -C 6 alkyl;
X 1 is S;
R 3 is ethyl; and
R 4 and R 5 are each methyl.
7. The compound of claim 1 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 3 -C 6 alkyl;
X 1 is S;
R 3 is ethyl; and
R 4 and R 5 are each methyl.
8. A compound of Formula I
wherein
R 1 is
R 2 is
L 1 and L 2 are each independently a linear C 1 -C 3 alkyl;
X 1 is S;
R 3 is linear C 1 -C 3 alkyl; and
R 4 and R 5 are each independently a C 1 -C 2 alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
9. The compound of claim 8 , wherein L 1 and L 2 are each independently C 1 -C 3 alkyl.
10. The compound of claim 8 , wherein R 3 is ethyl, propyl or butyl.
11. The compound of claim 8 , wherein R 4 and R 5 are each independently methyl or ethyl.
12. The compound of claim 8 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 1 -C 3 alkyl;
X 1 is S;
R 3 is a linear C 4 alkyl; and
R 4 and R 5 are each ethyl.
13. The compound of claim 8 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 1 -C 3 alkyl;
X 1 is S;
R 3 is a linear C 3 alkyl; and
R 4 and R 5 are each ethyl.
14. The compound of claim 8 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 1 -C 3 alkyl;
X 1 is S;
R 3 is ethyl; and
R 4 and R 5 are each methyl.
15. The compound of claim 8 , wherein
R 1 is
R 2 is
L 1 and L 2 are each C 1 -C 3 alkyl;
X 1 is S;
R 3 is a C 3 alkyl; and
R 4 and R 5 are each methyl.
16. A pharmaceutical composition comprising the compound of claim 1 .
17. The pharmaceutical composition of claim 16 , wherein the compound is in a lipid nanoparticle and wherein the lipid nanoparticle encapsulates a mRNA.
18. The pharmaceutical composition of claim 17 , wherein the lipid nanoparticle further comprises a neutral lipid and/or a conjugated lipid.
19. The pharmaceutical composition of claim 18 , further comprising a mRNA encoding a biologically active protein.
20. The pharmaceutical composition of claim 19 , further comprising an RNA comprising a nucleotide sequence homologous to a mRNA in a target cell.