Lipid prodrugs of mycophenolic acid and uses thereof
Inventors
Bonner, Daniel Kenneth • Karanam, Ketki • Han, Sifei • Hu, Luojuan • Porter, Christopher John Hamilton • Quach, Tim • Shyam, Rishab R. • Simpson, Jamie • Trevaskis, Natalie
Assignees
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Publication Number
US-11304954-B2
Publication Date
2022-04-19
Expiration Date
Abstract
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, and methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
Core Innovation
The invention relates to compounds of Formula VI, or pharmaceutically acceptable salts thereof, in which the therapeutic agent A is selected from mycophenolic acid or a derivative, analogue, or prodrug thereof. The compounds are defined by variable substituents R1, R2, and R3, a heteroatom-containing group X, an optional group Y, and a linker L that is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain. The scaffold further includes a self-immolative group -M-, with n being 0-18 and m being independently 0-6.
Within Formula VI, R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3, and each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain. X is selected from -O-, -NR-, and -S-, together with heteroatom-linked variants incorporating C1-6 aliphatic groups with optional replacement of 0-2 methylene units by -O-, -NR-, or -S-, and optional substitution with 1, 2, or 3 deuterium or halogen atoms. Y is absent or is -C(O)-, -C(NR)-, or -C(S)-.
The linker portion L is defined with 0-8 methylene units independently replaced by -Cy-, -O-, -NR-, -S-, OC(O), C(O)O-, C(O)-, S(O)-, S(O)2-, C(S)-, NRS(O)2-, S(O)2NR-, NRC(O)-, OC(O)NR-, NRC(O)O-, or an amino acid, and 1 methylene unit of L is optionally replaced with -M-, where -M- is a self-immolative group. L is attached to A on either the right-hand side or the left-hand side, and the disclosure combines this therapeutic agent with lipid and self-immolative linker architectures, including lipid prodrugs of mycophenolic acid and self-immolative TG/phenol prodrugs.
Claims Coverage
The claim coverage centers on a Formula VI compound class with a mycophenolic acid-based therapeutic agent A. The coverage includes at least three structural variable regions: R1/R2/R3, X/Y, and linker L with optional self-immolative group -M-, and the related dependent claims further narrow these features and recite therapeutic use.
Formula VI compound with variable R1/R2/R3 and mycophenolic acid-based therapeutic agent
A compound of Formula VI (or pharmaceutically acceptable salt thereof) wherein R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3; each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain; and A is a therapeutic agent selected from mycophenolic acid or a derivative, analogue, or prodrug thereof.
Heteroatom pattern X and optional Y constraint
X is selected from -O-, -NR-, and -S-, and heteroatom-linked variants incorporating C1-6 aliphatic groups with optional replacement of 0-2 methylene units by -O-, -NR-, or -S-, and optional substitution with 1, 2, or 3 deuterium or halogen atoms; Y is absent or -C(O)-, -C(NR)-, or -C(S)-.
Linker L including optional self-immolative group -M-
L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units are independently replaced by -Cy-, -O-, -NR-, -S-, OC(O), C(O)O-, C(O)-, S(O)-, S(O)2-, C(S)-, NRS(O)2-, S(O)2NR-, NRC(O)-, OC(O)NR-, NRC(O)O-, or an amino acid, and wherein 1 methylene unit of L is optionally replaced with -M-, where -M- is a self-immolative group.
Therapeutic use for treating autoimmune disease
A method of treating an autoimmune disease, disorder, or condition in a patient by administering an effective amount of a compound (or pharmaceutically acceptable salt thereof) as defined in claim 1.
Overall, the claims define a Formula VI compound class built around a mycophenolic acid-related therapeutic agent A, variable R1/R2/R3 and X/Y selections, and a linker L that may include the self-immolative group -M-. Dependent claims narrow the scaffold further through fixed X/Y selections, constrained linker and substituent options, and treatment of autoimmune disease.
Stated Advantages
Improved lymphatic transport.
Reduced first-pass metabolism.
Reduced toxicity and GI irritation.
Enhance oral bioavailability.
Immune response modulation and treatment of hyperinflammation.
Potentially enable CNS/BBB delivery via lymphatics.
Documented Applications
Treating an autoimmune disease, disorder, or condition in a patient by administering an effective amount of the compound or lipid prodrug.
Lipid prodrugs of mycophenolic acid are described in the context of lymphatic-directed delivery and immune-cell delivery, including B and T lymphocytes, dendritic cells, granulocytes, innate lymphoid cells (ILCs), monocytes/macrophages, and natural killer (NK) cells.
Treatment methods are described for autoimmune disease, disorder, or condition, including systemic lupus erythematosus (SLE), lupus nephritis (LN), celiac disease, and inflammatory bowel disease (IBD).
Transplant-related applications are described, including preventing transplant rejection and addressing graft-versus-host disease (GVHD).
Treating transplant rejection.
Treating graft-versus-host disease (GVHD).
Treating gut inflammation/IBD, including Crohn’s disease and ulcerative colitis.
Treating celiac disease.
Treating SLE and lupus nephritis.
Treating multiple sclerosis.
Treating rheumatoid arthritis.
Treating asthma.
Treating transplantation-related conditions.
Therapeutic methods for immune modulation involving B/T lymphocytes and macrophage activation, including hyperinflammation contexts.
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