Lipid prodrugs of rapamycin and its analogs and uses thereof
Inventors
Bonner, Daniel Kenneth • Han, Sifei • Hu, Luojuan • Karanam, Ketki • PORTER, Christopher John • Quach, Tim • Shyam, Rishab R. • Simpson, Jamie • Trevaskis, Natalie
Assignees
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Publication Number
US-11608345-B1
Publication Date
2023-03-21
Expiration Date
Abstract
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as 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 11, or pharmaceutically acceptable salts thereof, including rapamycin analog compounds and rapamycin macrolide analogs as lipid prodrugs. The compound framework includes multiple positions independently hydrogen or deuterium, Ra through Rh selected from methyl and deuterated methyl groups, and R1, R14, and R35 independently hydrogen, deuterium, or a chemical entity of Formula 1, provided that at least one of R1, R14, and R35 is a chemical entity of Formula 1.
The disclosed structures include A, X, L, Y, and a self-immolative group -M-, with L defined as a covalent bond or a bivalent hydrocarbon chain and with one methylene unit of L optionally replaced with -M-. X is selected from oxygen-, nitrogen-, and sulfur-containing link options, Y is absent or selected from carbonyl-related linkages, and n and m are defined as integer ranges. The disclosure also describes acetal self-immolative groups and related linker concepts, together with lipid prodrug scaffolds using acid-labile groups, lipids, and carbonyl-linked substituents.
The invention is positioned as a lipid prodrug strategy that reduces first-pass effect and is described as improving bioavailability and therapeutic index. It is further framed as an immunomodulatory approach that reduces macrophage activation and reduces T-cell activation and infiltration, and it includes pharmaceutical compositions and therapeutic methods for transplant rejection, hyperinflammation-associated conditions, and autoimmune disease.
Claims Coverage
The consolidated claim coverage centers on a Formula 11 compound genus with extensive substituent freedom and a defined A/X/L/Y scaffold including the self-immolative group -M-. The claim set also includes methods of use for administering the claimed compound in transplant rejection, hyperinflammation-associated conditions, and autoimmune disease.
Formula 11 compound with hydrogen, deuterium, and Formula 1 substituent scope
A compound of Formula 11, or a pharmaceutically acceptable salt thereof, wherein multiple R positions are independently H or D, Ra through Rh are independently selected from -CH3, -CH2D, -CHD2, and -CD3, and each of R1, R14, and R35 is independently H, D, or a chemical entity of Formula 1, with at least one of R1, R14, and R35 being a chemical entity of Formula 1.
A-X-Y-L scaffold with self-immolative group -M-
The compound includes A, X, Y, L, and -M-, where X is selected from multiple oxygen-, nitrogen-, and sulfur-containing link options, Y is absent or selected from -C(O)-, -C(NR')-, or -C(S)-, L is a covalent bond or a bivalent hydrocarbon chain with optional replacements and substitutions, and one methylene unit of L is optionally replaced with -M- as a self-immolative group; n and m are defined by integer ranges.
R1', R2', R3', R4', and R5' substituent definitions
R1' and R2' are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R3'; R3' is a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain; and R4' and R5' each independently include hydrogen, deuterium, halogen, -CN, -OR', -NR'2, -SR', and specified monocyclic or bicyclic carbocyclic or heterocyclic substituent classes.
The claims consolidate around a Formula 11 compound genus defined by hydrogen/deuterium substitution, Formula 1 incorporation at one of R1, R14, or R35, and a linker architecture built from A, X, L, Y, and the self-immolative group -M-. The claim set also extends to methods of use for administering the compound in transplant rejection, hyperinflammation-associated conditions, and autoimmune disease.
Stated Advantages
Reduces a first-pass effect.
Improves bioavailability.
Improves the therapeutic index.
Reduces macrophage activation.
Reduces T-cell activation and infiltration.
Documented Applications
Treating or preventing organ transplant rejection in a patient in need thereof by administering the compound.
Treating a disease, disorder, or condition associated with hyperinflammation in a patient in need thereof by administering the compound.
Treating an autoimmune disease, disorder, or condition in a patient in need thereof by administering the compound.
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