Cationic lipids for use in lipid nanoparticles
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein a, b, c, d, G 1 , G 2 , L 1 , L 2 , R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 and X are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, nanoparticles comprising the compounds and methods for their use and preparation are also provided.
1. A compound having a structure of Formula (I):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
G 1 and G 2 are each independently C 1 -C 6 alkylene;
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—;
R 1a and R 1b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 1a is H or C 1 -C 12 alkyl, and R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 2a and R 2b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 2a is H or C 1 -C 12 alkyl, and R 2b together with the carbon atom to which it is bound is taken together with an adjacent R 2b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 3a and R 3b are, at each occurrence, independently either (a): H or C 1 -C 12 alkyl; or (b) R 3a is H or C 1 -C 12 alkyl, and R 3b together with the carbon atom to which it is bound is taken together with an adjacent R 3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 4a and R 4b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 4a is H or C 1 -C 12 alkyl, and R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 5 and R 6 are each independently H or methyl;
R 7 is —O(C═O)R 10 , —(C═O)OR 10 , —NR 9 (C═O)R 10 or —(C═O)NR 9 R 10 ;
R 8 is OH, —N(R 11 )(C═O)R 12 , —(C═O)NR 11 R 12 , —NR 11 R 12 , —(C═O)OR 12 or —O(C═O)R 12 ;
R 9 is H or C 1 -C 15 alkyl;
R 10 is C 1 -C 15 alkyl;
R 11 is H or C 1 -C 6 alkyl;
R 12 is C 1 -C 6 alkyl;
X is —(C═O)— or a direct bond; and
a, b, c and d are each independently an integer from 1 to 24;
wherein each methyl, alkyl and alkylene is independently optionally substituted.
2. The compound of claim 1 , having one of the following structures (IA) or (IB):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
3. The compound of claim 1 , wherein G 1 is C 2 -C 3 alkylene or C 4 -C 6 alkylene.
4. The compound of claim 1 , wherein G 2 is C 2 -C 3 alkylene or C 3 -C 4 alkylene.
5. The compound of claim 1 , wherein X is a direct bond.
6. The compound of any one of claim 1 , wherein R 7 is —O(C═O)R 10 or —(C═O)OR 10 .
7. The compound of claim 6 , wherein R 10 is linear C 6 -C 10 alkyl.
8. The compound of claim 6 , wherein R 10 is methyl.
9. The compound of claim 6 , wherein R 10 is branched C 10 -C 15 alkyl.
10. The compound of any one of claim 1 , wherein R 7 is —NR 9 (C═O) or —(C═O)NR 9 R 10 .
11. The compound of claim 10 , wherein R 9 is H.
12. The compound of claim 10 , wherein R 9 and R 10 are each independently C 6 -C 10 alkyl.
13. The compound of claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are, at each occurrence, independently H or C 1 -C 12 alkyl.
14. The compound of claim 13 , wherein at least one of R 1b and R 4b is C 1 -C 8 alkyl.
15. The compound of claim 1 , wherein
or both, independently has one of the following structures:
16. The compound of claim 1 , wherein a, b, c and d are each independently an integer from 2 to 12.
17. The compound of claim 1 , wherein R 8 is —N(R 11 )(C═O)R 12 .
18. The compound of claim 1 , wherein R 8 is —(C═O)N 11 R 12 .
19. The compound of claim 1 , wherein R 8 is —NR 11 R 12 .
20. The compound of claim 1 , wherein R 8 is —(C═O)OR 12 .
21. The compound of claim 20 , wherein R 8 is —O(C═O)R 12 .
22. The compound of claim 1 , wherein R 8 has one of the following structures:
23. The compound of claim 1 , having one of the following structures:
24. A lipid nanoparticle comprising the compound of claim 1 and an mRNA encoding a protein.
25. A pharmaceutical composition comprising the lipid nanoparticle of claim 24 and a pharmaceutically acceptable diluent or excipient.
26. A method for expressing a protein in a patient in need thereof, the method comprising administering the lipid nanoparticle of claim 24 to the patient, wherein the protein encoded by the mRNA is expressed in the patient.
27. A method for vaccinating a patient in need thereof against a viral pathogen, the method comprising administering the lipid nanoparticle of claim 24 to the patient, wherein the protein is a viral antigen.