IONIZABLE LIPIDS WITH BRANCHED HEAD GROUPS
The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and/or nanomaterials and methods of their use such as a compound of Formula (A) or a pharmaceutically acceptable salt thereof.
1 . A compound having a structure according to Formula (A),
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is a covalent bond, —O—, or —NH—;
X 2 is —C(O)—, —OC(O)O—, —C(O)O—, —OC(O)—, —NHC(O)O—, or —OC(O)NH—;
X 3 is —NR 1 R 2 , a 5- to 6-membered nitrogen-containing heterocycle, or a 5- to 6-membered nitrogen-containing heteroaryl;
each of Y 1 and Y 2 is independently —C(O)—, —OC(O)O—, —C(O)O—, or —OC(O)—;
L 1 is (CR 7 R 8 ) o ;
L 2 is C 2 -C 6 alkylene;
each of L 3 and L 4 is independently C 2 -C 8 alkylene;
each of R 1 and R 2 is independently H or C 1 -C 6 alkyl;
each of R 3 and R 5 is independently H, C 4 -C 20 alkyl, C 2 -C 20 alkenyl, or C 4 -C 20 alkynyl;
each of R 4 and R 6 is independently C 4 -C 20 alkyl, C 2 -C 20 alkenyl, or C 4 -C 20 alkynyl;
each of R 7 and R 8 is independently H or C 1 -C 8 alkyl, wherein at least one R 7 or R 8 is C 1 -C 8 alkyl;
each of R 9 and R 10 is independently H or C 1 -C 6 alkyl;
each of m and n is independently an integer of 0-4; and
o is an integer of 2-6.
2 . The compound of claim, wherein
each of R 9 and R 0 is H;
and/or
each of R 3 , R 4 , R 5 , and R 6 is independently C 4 -C 16 alkyl, C 4 -C 16 alkenyl, or C 4 -C 16 alkynyl, or each of R 3 , R 4 , R 5 , and R 6 is independently C 4 -C 20 alkyl, C 4 -C 20 alkenyl, or C 4 -C 20 alkynyl.
3 . The compound of claim or, having a structure according to Formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is a covalent bond, —O—, or —NH—;
X 2 is —C(O)—, —OC(O)O—, —C(O)O—, —OC(O)—, —NHC(O)O—, or —OC(O)NH—;
X 3 is —NR 1 R 2 , a 5- to 6-membered nitrogen-containing heterocycle, or a 5- to 6-membered nitrogen-containing heteroaryl;
each of Y 1 and Y 2 is independently —C(O)—, —OC(O)O—, —C(O)O—, or —OC(O)—;
L 1 is (CR 7 R 8 ) o ;
L 2 is C 2 -C 6 alkylene;
each of L 3 and L 4 is independently C 2 -C 8 alkylene;
each of R 1 and R 2 is independently H or C 1 -C 6 alkyl;
each of R 3 , R 4 , R 5 , and R 6 is independently C 4 -C 16 alkyl, C 4 -C 16 alkenyl, or C 4 -C 16 alkynyl;
each of R 7 and R 8 is independently H or C 1 -C 5 alkyl, wherein at least one R 7 or R 8 is C 1 -C 5 alkyl;
each of m and n is independently an integer of 0-4; and
o is an integer of 2-6.
4 . The compound of claim, wherein X 1 is a covalent bond.
5 . The compound any one of claims—, wherein X 2 is —NHC(O)O— or —OC(O)NH—.
6 . The compound of any one of claims—, wherein each of Y 1 and Y 2 is independently —C(O)O— or —OC(O)—.
7 . The compound of any one of claims—, wherein L 2 is (CH 2 ) 2 , (CH 2 ) 3 , or (CH 2 ) 4 .
8 . The compound of any one of claims—, wherein each of m and n is 0 or 1.
9 . The compound of any one of claims—, wherein m and n are the same.
10 . The compound of any one of claims—, wherein o is 2, 3, or 4.
11 . The compound of any one of claims—, wherein one and only one R 7 or R 8 is C 1 -C 8 alkyl.
12 . The compound of claim, having a structure according to Formula (II),
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim, having a structure according to Formula (III),
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim, having a structure according to Formula (IV),
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim, having a structure according to Formula (V),
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim, having a structure according to Formula (VI),
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim, having a structure according to Formula (VII),
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim, having a structure according to Formula (VIII),
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim, having a structure according to Formula (IX),
or a pharmaceutically acceptable salt thereof.
20 . The compound of any one of claims—, wherein each of L 3 and L 4 is independently (CH 2 ) 4 , (CH 2 ) 5 , or (CH 2 ) 6 .
21 . The compound of any one of claims—, wherein L 3 and L 4 are the same.
22 . The compound of any one of claims—, comprising a R 7 group that is C 4 -C 8 alkyl.
23 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 16 alkyl.
24 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 20 alkyl.
25 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 16 alkenyl.
26 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 20 alkenyl.
27 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 16 alkynyl.
28 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is independently C 6 -C 20 alkynyl.
29 . The compound of any one of claims—, wherein each of R 3 , R 4 , R 5 , and R 6 is —(CH 2 ) 3 CH═CH 2 , —(CH 2 ) 3 CH═C(H)CH 2 CH 3 , or —(CH 2 ) 5 CH═CH 2 .
30 . The compound of any one of claims—, wherein R 3 and R 4 are the same.
31 . The compound of any one of claims—, wherein R 5 and R 6 are the same.
32 . The compound of claim, having a structure according to Formula (X),
or a pharmaceutically acceptable salt thereof, wherein each of R 4 and R 6 is C 6 -C 20 alkenyl, or each of R 4 and R 6 is C 6 -C 20 alkyl.
33 . The compound of claim, wherein each of R 4 and R 6 is selected from the group consisting of
34 . The compound of claim or, wherein R 4 and R 6 are the same.
35 . The compound of claim 1 , wherein each of R 3 and R 5 is independently C 2 -C 4 alkenyl and each of R 9 and R 10 is independently H or C 1 -C 6 alkyl.
36 . The compound of claim or, having a structure according to Formula (XI),
or a pharmaceutically acceptable salt thereof, wherein each of R 4 and R 6 is C 6 -C 20 alkenyl, or each of R 4 and R 6 is C 6 -C 20 alkyl.
37 . The compound of claim or, having a structure according to Formula (XII),
or a pharmaceutically acceptable salt thereof, wherein each of R 4 and R 6 is C 6 -C 20 alkenyl, or each of R 4 and R 6 is C 6 -C 20 alkyl.
38 . The compound of claim or, wherein each of R 4 and R 6 is selected from the group consisting of
39 . The compound of any one of claims—, wherein R 4 and R 6 are the same.
40 . The compound of any one of claims—, wherein each of L 3 and L 4 is independently (CH 2 ) 4 , (CH 2 ) 5 , or (CH 2 ) 6 .
41 . The compound of any one of claims—, wherein L 3 and L 4 are the same.
42 . The compound of any one of claims—, wherein X 3 is —NR 1 R 2 , wherein each of R 1 and R 2 is independently H, CH 3 , or CH 2 CH 3 .
43 . The compound of any one of claims—, wherein X 3 is a 5- to 6-membered nitrogen-containing heterocycle.
44 . The compound of claim, wherein X 3 is
45 . The compound of any one of claims—, wherein X 3 is a 5- to 6-membered nitrogen-containing heteroaryl.
46 . The compound of claim, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
47 . The compound of claim selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
48 . The compound of claim, selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
49 . A lipid nanoparticle (LNP) preparation comprising a compound according to any one of claims—.
50 . A lipid nanoparticle (LNP) preparation comprising:
a compound according to any one of claims—;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid (e.g., polyethylene glycol lipid).
51 . The LNP preparation of claim or, further comprising a therapeutic and/or prophylactic agent.
52 . The LNP preparation of any one of claims—, wherein the therapeutic and/or prophylactic agent is or comprises one or more nucleic acids.
53 . The LNP preparation of claim, wherein the one or more nucleic acids is or comprises RNA.
54 . The LNP preparation of claim, wherein the one or more nucleic acids is or comprises DNA.
55 . The LNP preparation of any one of claims—, wherein the LNP preparation is formulated to deliver the therapeutic and/or prophylactic agent to target cells.
56 . The LNP preparation of claim wherein the target cells are or comprise spleen cells (e.g., splenic B cells, splenic T cells, splenic monocytes), liver cells (e.g., hepatocytes), bone marrow cells (e.g., bone marrow monocytes), immune cells, muscle cells (e.g., myocytes), heart cells (e.g., cardiomyocytes), kidney cells, or cells in the central nervous system.
57 . The LNP preparation of claim, wherein the target cells are or comprise hematopoietic stem cells.
58 . The LNP preparation of claim, wherein the target cells are or comprise liver cells.
59 . A pharmaceutical composition comprising a LNP preparation of any one of claims—and a pharmaceutically acceptable excipient.
60 . A method for administering a therapeutic and/or prophylactic agent to a subject in need thereof, the method comprising administering the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found. to the subject.
61 . A method for treating a disease or a disorder in a subject in need thereof, the method comprising administering the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found. to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
62 . A method for delaying and/or arresting progression a disease or a disorder in a subject in need thereof, the method comprising administering the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found. to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
63 . A method of delivering a therapeutic and/or prophylactic agent to a mammalian cell derived from a subject, the method comprising contacting the cell of the subject having been administered the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found.
64 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found., wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
65 . A method of inhibiting production of a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found., wherein the therapeutic and/or prophylactic agent is or comprises an RNA, whereby the RNA is capable of inhibiting production of the polypeptide of interest.
66 . A method of specifically delivering a therapeutic and/or prophylactic agent to a mammalian organ, the method comprising contacting a mammalian organ with the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found., whereby the therapeutic and/or prophylactic agent is delivered to the organ.
67 . The method of claim, comprising administering to a subject the LNP preparation of any one of claims—Error! Reference source not found. or the pharmaceutical composition of claim Error! Reference source not found. to the subject.
68 . A method of vaccinating by administering the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found.
69 . A method of inducing an adaptive immune response in a subject, comprising administering to the subject an effective amount of a composition comprising at least one RNA; wherein the composition comprises a LNP preparation comprising a compound of any one of claims 1 —, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.
70 . The method of claim, wherein the LNP preparation is the LNP preparation of any one of claims—Error! Reference source not found. and/or the pharmaceutical composition is the pharmaceutical composition of claim Error! Reference source not found.
71 . A method of base editing a genome of a cell, the method comprising contacting the cell of the subject having been administered the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found.
72 . A method of base editing a genome of a cell in a subject, the method comprising administering to the subject an effective amount of a composition comprising the LNP preparation of any one of claims—or the pharmaceutical composition of claim Error! Reference source not found.