Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , G 1 , G 2 , G 3 , a, b, c and d 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 a structure of Formula IA or IB:
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, —SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, —NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O—;
G 3 is C 1 -C 6 alkylene;
R a is H or C 1 -C 12 alkyl;
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 C 6 -C 16 alkyl;
R 8 and R 9 are each independently C 1 -C 12 alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;
a, b, c and d are each independently an integer from 1 to 24; and
x is 0, 1 or 2.
2. The compound of claim 1 , wherein:
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—.
3. The compound of claim 1 , having a structure of formula (IA).
4. The compound of claim 1 , wherein one of L 1 or L 2 is —O(C═O)—.
5. The compound of claim 4 , wherein each of L 1 and L 2 are —O(C═O)—.
6. The compound of claim 1 , wherein one of L 1 or L 2 is —(C═O)O—.
7. The compound of claim 6 , wherein each of L 1 and L 2 is —(C═O)O—.
8. The compound of claim 1 , wherein for at least one occurrence of R 1a and R 1b , 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.
9. The compound of claim 1 , wherein for at least one occurrence of R 4a and R 4b , 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.
10. The compound of claim 1 , wherein for at least one occurrence of R 2a and R 2b , 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.
11. The compound of claim 1 , wherein for at least one occurrence of R 3a and R 3b , 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.
12. The compound of claim 1 , wherein a, b, c and d are each independently an integer from 2 to 12.
13. The compound of claim 12 , wherein a, b, c and d are each independently an integer from 5 to 9.
14. The compound of claim 1 , wherein at least one of R 1a , R 2a , R 3a and R 4a is H.
15. The compound of claim 1 , wherein R 1a , R 2a , R 3a and R 4a are H at each occurrence.
16. The compound of claim 1 , wherein at least one of R 1a , R 2a , R 3a and R 4a is C 1 -C 8 alkyl.
17. The compound of claim 16 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
18. The compound of claim 1 , wherein at least one of R 1b , R 2b , R 3b and R 4b is H.
19. The compound of claim 1 , wherein R 1b , R 2b , R 3b and R 4b are H at each occurrence.
20. The compound of claim 1 , wherein one of R 5 or R 6 is methyl.
21. The compound of claim 1 , wherein each of R 5 and R 6 is methyl.
22. The compound of claim 1 , wherein R 7 is C 6 -C 9 alkyl.
23. The compound of claim 1 , wherein R 7 is substituted with —(C═O)OR b , —O(C═O)R b , —C(═O)R b , —OR b , —S(O) x R b , —S—SR b , —C(═O)SR b , —SC(═O)R b , —NR a R b , —NR a C(═O)R b , —C(═O)NR a R b , —NR a C(═O)NR a R b , —OC(═O)NR a R b , —NR a C(═O)OR b , —NR a S(O) x NR a R b , —NR a S(O) x R b or —S(O) x NR a R b , wherein: R a is H or C 1 -C 12 alkyl; R b is C 1 -C 15 alkyl; and x is 0, 1 or 2.
24. The compound of claim 23 , wherein R 7 is substituted with —(C═O)OR b or —O(C═O)R b .
25. The compound of claim 23 , wherein R b is branched C 1 -C 15 alkyl.
26. The compound of claim 25 , wherein R b has one of the following structures:
27. The compound of claim 1 , wherein at least one of R 8 or R 9 is methyl.
28. The compound of claim 27 , wherein each of R 8 and R 9 is methyl.
29. The compound of claim 1 , wherein R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring.
30. The compound of claim 29 , wherein the heterocyclic ring is pyrrolidinyl.
31. The compound of claim 29 , wherein the heterocyclic ring is piperazinyl.
32. The compound of claim 1 , wherein G 3 is C 2 -C 4 alkylene.
33. The compound of claim 1 , wherein G 3 is C 3 alkylene.
34. The compound of claim 1 , having one of the following structures:
35. A composition comprising the compound of claim 1 and a therapeutic agent.
36. The composition of claim 35 , further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.
37. The composition of claim 36 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.
38. The composition of claim 37 , wherein the neutral lipid is DSPC.
39. The composition of claim 36 , wherein the steroid is cholesterol.
40. The composition of claim 39 , wherein the molar ratio of the compound to cholesterol ranges from about 2:1 to 1:1.
41. The composition of claim 36 , wherein the polymer conjugated lipid is a pegylated lipid.
42. The composition of claim 41 , wherein the molar ratio of the compound to the pegylated lipid ranges from about 100:1 to about 25:1.
43. The composition of claim 41 , wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.
44. The composition of claim 41 , wherein the pegylated lipid has the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and
z has a mean value ranging from 30 to 60.
45. The composition of claim 44 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.
46. The composition of claim 44 , wherein the average z is about 45.
47. The composition of claim 35 , wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.
48. The composition of claim 35 , wherein the therapeutic agent comprises a nucleic acid.
49. The composition of claim 48 , wherein the nucleic acid is selected from antisense and messenger RNA.
50. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 35 and administering the composition to the patient.
51. The compound of claim 1 , having a structure of formula (IB).