Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure (I) or (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R, R 1 , R 2 , L, X, L, G 1 , G 2 , Z, a 1 , a 2 and n are independently as defined herein for each of structures (I) and (II). 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 or stereoisomer thereof, wherein:
L is, at each occurrence, ~O(C═O)—, wherein ~ represents a covalent bond to X;
X is CH;
Z is C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is substituted with C 1 -C 6 alkylaminyl;
R is, at each occurrence, H;
R 1 and R 2 independently have one of the following structures:
and
a 1 and a 2 are, at each occurrence, independently an integer from 4 to 9.
2 . The compound of claim 1 , wherein the compound has the structures:
3 . The compound of claim 1 , wherein Z, has the structures:
4 . The compound of claim 1 , wherein Z-L has the structures:
5 . The compound of claim 1 , having the structures:
6 . A composition comprising the compound of claim 1 and a therapeutic agent.
7 . A method for administering a therapeutic agent to a patient in need thereof, the method comprising administering the composition of claim 6 to the patient.
8 . The composition of claim 6 , wherein the therapeutic agent is messenger RNA (mRNA).
9 . A lipid nanoparticle comprising the compound of claim 1 and a therapeutic agent.
10 . The lipid nanoparticle of claim 9 , wherein the therapeutic agent is messenger RNA (mRNA).
11 . The compound of claim 1 , wherein Z, has the structures: