Lipids for use in lipid nanoparticle formulations
Compounds are provided having the following structure (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein X, Y, L 1 , L 2 , L 3 , G 1 , G 2 and G 3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
1. A compound having the following structure (I):
or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:
X is N, and Y is absent; or X is CR, and Y is NR;
L 1 is —O(C═O)R 1 , —(C═O)OR 1 , —C(═O)R 1 , —OR 1 , —S(O) x R 1 , —S—SR 1 , —C(═O)SR 1 , —SC(═O)R 1 , —NR a C(═O)R 1 , —C(═O)NR b R c , —NR a C(═O)NR b R c , —OC(═O)NR b R c or —NR a C(═O)OR 1 ;
L 2 is —O(C═O)R 2 , —(C═O)OR 2 , —C(═O)R 2 , —OR 2 , —S(O) x R 2 , —S—SR 2 , —C(═O)SR 2 , —SC(═O)R 2 , —NR d C(═O)R 2 , —C(═O)NR e R f , —NR d C(═O)NR e R f , —OC(═O)NR e R f ; —NR d C(═O)OR 2 or a direct bond to R 2 ;
L 3 is —O(C═O)R 3 or —(C═O)OR 3 ;
G 1 and G 2 are each independently C 2 -C 12 alkylene or C 2 -C 12 alkenylene;
G 3 is C 1 -C 8 alkylene, C 2 -C 8 alkenylene, C 1 -C 8 heteroalkylene or C 2 -C 8 heteroalkenylene when X is CR, and Y is NR; and G 3 is unsubstituted C 1 -C 8 heteroalkylene or unsubstituted C 2 -C 8 heteroalkenylene when X is N, and Y is absent;
R a , R b , R d and R e are each independently H or C 1 -C 12 alkyl or C 1 -C 12 alkenyl;
R c and R f are each independently C 1 -C 12 alkyl or C 2 -C 12 alkenyl;
each R is independently H or unsubstituted C 1 -C 12 alkyl;
R 1 , R 2 and R 3 are each independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; and
x is 0, 1 or 2.
2. The compound of claim 1 , wherein G 3 is C 1 -C 8 alkylene.
3. The compound of claim 1 , wherein G 3 is unsubstituted C 1 -C 8 heteroalkylene.
4. The compound of claim 3 , wherein G 3 is C 1 -C 8 aminylalkylene.
5. The compound of claim 1 , wherein X is N and Y is absent.
6. The compound of claim 1 , wherein X is CR and Y is NR.
7. The compound of claim 1 , having one of the following structures (IA), (IB), (IC) or (ID):
8. The compound of claim 1 , wherein L 1 is —O(C═O)R 1 , —(C═O)OR 1 or —C(═O)NR b R c , and L 2 is —O(C═O)R 2 , —(C═O)OR 2 or —C(═O)NR e R f .
9. The compound of claim 8 , wherein L 1 is —(C═O)OR 1 and L 2 is —(C═O)OR 2 .
10. The compound of claim 1 , wherein L 3 is —(C═O)OR 3 .
11. The compound of claim 1 , wherein G 1 and G 2 are each independently C 4 -C 10 alkylene.
12. The compound of claim 1 , wherein R 1 , R 2 and R 3 are each, independently, branched C 6 -C 24 alkyl.
13. The compound of claim 12 , wherein R 1 , R 2 and R 3 each, independently have the following structure:
wherein:
R 7a and R 7b are, at each occurrence, independently H or C 1 -C 12 alkyl; and
a is an integer from 2 to 12,
wherein R 7a , R 7b and a are each selected such that R 1 and R 2 are each independently branched and independently comprise from 6 to 20 carbon atoms.
14. The compound of claim 13 , wherein a is an integer from 8 to 12.
15. The compound of claim 13 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
16. The compound of claim 1 , wherein X is CR, Y is NR and R 3 is C 1 -C 12 alkyl.
17. The compound of claim 1 , wherein R 1 , R 2 and R 3 independently have one of the following structures:
18. The compound of claim 1 , having one of the following structures:
19. A composition comprising the compound of claim 1 and a therapeutic agent.
20. The composition of claim 19 , wherein the therapeutic agent comprises a nucleic acid.
21. The composition of claim 20 , wherein the nucleic acid is selected from antisense and messenger RNA.
22. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 19 , and administering the composition to the patient.
23. A lipid nanoparticle comprising the compound of claim 1 .
24. A pharmaceutical composition comprising the lipid nanoparticle of claim 23 and a pharmaceutically acceptable diluent or excipient.