IONIZABLE AMINE AND ESTER LIPIDS AND LIPID NANOPARTICLES
The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and/or nanomaterials and methods of their use.
1 . A compound of formula I′:
or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein
each of X 1 and X 1′ is independently —NH— or —O—;
each of L 1 and L 1′ is independently an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —;
each of X 2 and X 2′ is independently —CH— or N;
each of L 2 and L 2′ is independently an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —;
each of X 3 and X 3′ is independently absent, —OC(O)—, —C(O)O—, or —OC(O)O—;
each of R 1 and R 1′ is independently
or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered saturated or partially unsaturated carbocyclyl, 7- to 12-membered saturated or partially unsaturated bridged bicyclyl having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
each of L 3 and L 3′ is independently absent or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —;
each of X 4 and X 4′ is independently absent, —OC(O)—, —C(O)O—, or —OC(O)O—;
each of R 2 and R 2′ is independently hydrogen,
or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered saturated or partially unsaturated carbocyclyl, 7- to 12-membered saturated or partially unsaturated bridged bicyclyl having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
each L 3a is independently absent or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —;
each R a is independently hydrogen or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered saturated or partially unsaturated carbocyclyl, 7- to 12-membered saturated or partially unsaturated bridged bicyclyl having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
each of L 5 and L 5′ is independently absent or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —;
each of L 6 and L 6′ is independently absent or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR b —; X 5 is absent or —C(O)O—;
L 4 is absent or C 1-6 alkylene;
Y is absent, hydrogen, —NR 2 , 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur with at least one heteroatom being nitrogen, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur with at least one heteroatom being nitrogen;
each R is independently C 1-6 aliphatic; and
each R b is independently hydrogen or an optionally substituted C 1-6 aliphatic group;
provided that when X 2 and X 2′ are —CH—, then X 5 , L 4 , and Y must all be present.
2 . The compound of claim 1 , wherein the compound is of Formula I:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 2 , wherein the compound is of Formula I-A:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
4 . The compound of any one of claims 1-3 , wherein the compound is of Formula I-B:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
5 . The compound of any one of claims 1-3 , wherein the compound is of Formula I-C:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 or 2 , wherein the compound is of Formula I-D:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 , wherein the compound is of Formula I-E:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
8 . The compound of any one of claims 1-7 , wherein X 1 is —NH—.
9 . The compound of any one of claims 1-7 , wherein X 1 is —O—.
10 . The compound of any one of claims 1-9 , wherein X 1′ is —NH—.
11 . The compound of any one of claims 1-9 , wherein X 1′ is —O—.
12 . The compound of any one of claims 1-11 , wherein L 1 is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
13 . The compound of any one of claims 1-12 , wherein L 1′ is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
14 . The compound of any one of claims 1-13 , wherein X 2 is —CH—.
15 . The compound of any one of claims 1-13 , wherein X 2 is N.
16 . The compound of any one of claims 1-15 , wherein X 2′ is —CH—.
17 . The compound of any one of claims 1-15 , wherein X 2′ is N.
18 . The compound of any one of claims 1-17 , wherein L 2 is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
19 . The compound of any one of claims 1-18 , wherein L 2 is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
20 . The compound of any one of claims 1-19 , wherein X 3 is —OC(O)—.
21 . The compound of any one of claims 1-19 , wherein X 3 is absent.
22 . The compound of any one of claims 1-21 , wherein X 3′ is —C(O)O—.
23 . The compound of any one of claims 1-21 , wherein X 3′ is absent.
24 . The compound of any one of claims 1-23 , wherein R′ is optionally substituted C 6-20 aliphatic.
25 . The compound of any one of claims 1-23 , wherein R 1 is
26 . The compound of any one of claims 1-25 , wherein R″ is optionally substituted C 6-20 aliphatic.
27 . The compound of any one of claims 1-25 , wherein R 1′ is
28 . The compound of any one of claims 1-27 , wherein L 3 is absent.
29 . The compound of any one of claims 1-27 , wherein L 3 is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
30 . The compound of any one of claims 1-29 , wherein L 3′ is absent.
31 . The compound of any one of claims 1-29 , wherein L 3′ is an optionally substituted, bivalent saturated or unsaturated, straight or branched, C 1-10 hydrocarbon chain.
32 . The compound of any one of claims 1-31 , wherein X 4 is absent.
33 . The compound of any one of claims 1-31 , wherein X 4 is —OC(O)—.
34 . The compound of any one of claims 1-33 , wherein X 4′ is absent.
35 . The compound of any one of claims 1-33 , wherein X 4′ is —C(O)O—.
36 . The compound of any one of claims 1-35 , wherein R 2 is hydrogen.
37 . The compound of any one of claims 1-35 , wherein R 2 is optionally substituted C 6-20 aliphatic.
38 . The compound of any one of claims 1-35 , wherein R 2 is
39 . The compound of any one of claims 1-38 , wherein R 2′ is optionally substituted C 6-20 aliphatic.
40 . The compound of any one of claims 1-38 , wherein R 2′ is
41 . The compound of any one of claims 1-40 , wherein L 3a is absent.
42 . The compound of any one of claims 1-41 , wherein R a is optionally substituted C 6-20 aliphatic.
43 . The compound of any one of claims 1-42 , wherein X 5 is absent.
44 . The compound of any one of claims 1-42 , wherein X 5 is —C(O)O—.
45 . The compound of any one of claims 1-44 , wherein L 4 is absent.
46 . The compound of any one of claims 1-44 , wherein L 4 is C 1-6 alkylene.
47 . The compound of any one of claims 1-46 , wherein L 5 is absent.
48 . The compound of any one of claims 1-46 , wherein L 5 is a bivalent saturated, straight or branched C 1-6 hydrocarbon chain.
49 . The compound of any one of claims 1-48 , wherein L 5′ is absent.
50 . The compound of any one of claims 1-48 , wherein L 5′ is a bivalent saturated, straight or branched C 1-6 hydrocarbon chain.
51 . The compound of any one of claims 1-50 , wherein L 6 is absent.
52 . The compound of any one of claims 1-50 , wherein L 6 is a bivalent saturated, straight or branched C 1-6 hydrocarbon chain.
53 . The compound of any one of claims 1-52 , wherein L 6′ is absent.
54 . The compound of any one of claims 1-52 , wherein L 6′ is a bivalent saturated, straight or branched C 1-6 hydrocarbon chain.
55 . The compound of any one of claims 1-54 , wherein Y is absent.
56 . The compound of any one of claims 1-54 , wherein Y is —NR 2 .
57 . The compound of any one of claims 1-56 , wherein each R is independently C 1-6 aliphatic.
58 . A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
59 . A lipid nanoparticle (LNP) preparation comprising an ionizable lipid of any one of claims 1-58 .
60 . A lipid nanoparticle (LNP) preparation comprising:
an ionizable lipid of any one of claims 1-58 ;
a phospholipid;
a sterol; and
a conjugate-linker lipid (e.g., polyethylene glycol lipid).
61 . The LNP preparation of claim 59 or 60 , further comprising a therapeutic and/or prophylactic agent.
62 . The LNP preparation of claim 61 , wherein the therapeutic and/or prophylactic agent is or comprises one or more nucleic acids.
63 . The LNP preparation of claim 61 , wherein the one or more nucleic acids is or comprises RNA.
64 . The LNP preparation of claim 61 , wherein the one or more nucleic acids is or comprises DNA.
65 . The LNP preparation of any one of claims 61-64 , wherein the LNP preparation is formulated to deliver the therapeutic and/or prophylactic agent to target cells.
66 . The LNP preparation of claim 65 , 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, kidney cells, muscle cells, heart cells, lung cells, or cells in the central nervous system.
67 . The LNP preparation of claim 66 , wherein the target cells are or comprise hematopoietic stem cells (HSCs).
68 . A pharmaceutical composition comprising a LNP preparation of any one of claims 59-67 and a pharmaceutically acceptable excipient.
69 . 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 59-67 or the pharmaceutical composition of claim 68 to the subject.
70 . 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 59-67 , or the pharmaceutical composition of claim 68 , to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
71 . 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 59-67 , or the pharmaceutical composition of claim 68 , to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
72 . 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 59-67 , or the pharmaceutical composition of claim 68 .
73 . 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 59-67 , or the pharmaceutical composition of claim 68 , 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.
74 . 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 59-67 , or the pharmaceutical composition of claim 68 , 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.
75 . A method of specifically delivering a therapeutic and/or prophylactic agent to a mammalian organ, tissue, cell, or population of cells, the method comprising contacting a mammalian organ, tissue, cell, or population of cells with the LNP preparation of any one of claims 59-67 , or the pharmaceutical composition of claim 68 , whereby the therapeutic and/or prophylactic agent is delivered to the organ, tissue, cell, or population of cells.
76 . The method of claim 75 , comprising administering to a subject the LNP preparation of any one of claims 59-67 , or the pharmaceutical composition of claim 68 , to the subject.
77 . A method of vaccinating by administering the LNP preparation of any one of claims 59-67 , or the pharmaceutical composition of claim 68 .
78 . 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 1-58 , or a pharmaceutically acceptable salt thereof.