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Publication Number
US-11357856-B2
Publication Date
2022-06-14
Expiration Date
Abstract
Compounds are provided having the following structure: Formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R, R1, R2, G1, G2 and n are as defined herein. 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.
Core Innovation
The invention relates to a cationic amino lipid scaffold having a structure (I) defined by substituent variables R, R1, R2, G1, G2, and n. The scaffold specifies that G1 can be —OH, —NR3R4, —(C=O)NR5, or —NR3(C=O)R5, and that G2 can be —CH2— or —(C=O)—. The substituents R1 and R2 are each optionally substituted C12-C36 alkyl groups that are branched and saturated or unsaturated, R3 and R4 are each H or optionally substituted C1-C6 alkyl groups that are straight or branched and saturated or unsaturated, R5 is optionally substituted C1-C6 alkyl that is straight or branched and saturated or unsaturated, and n is an integer from 2 to 6.
The disclosure further provides embodiments of related sub-structures (IA) and (IB) with additional parameter ranges for alkyl substituents. These embodiments define further structural variations using additional substituent variables and constrained integer/range parameters for the relevant alkyl groups while remaining within the overall lipid scaffold framework.
The invention further relates to using the defined cationic (amino) lipids to form lipid nanoparticle formulations with neutral lipids, cholesterol/steroids, and polymer conjugated/PEGylated lipids. The stated goal is improved intracellular delivery and serum protection when delivering therapeutic agents, particularly nucleic acids including mRNA, antisense oligonucleotides, miRNA inhibitors, and siRNA.
Claims Coverage
The independent claim covers a compound defined by a specific structure (I) with defined inventive features in the ring/linker substituents (G1, G2), side-chain substituent classes (R1-R5), and the integer range of n. The listed independent and dependent scope also extends to a lipid nanoparticle delivery vehicle including the compound with a therapeutic agent.
Cationic amino lipid scaffold with defined structure (I) and substituent classes
A compound having the structure (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein G1 is —OH, —NR3R4, —(C=O)NR5, or —NR3(C=O)R5; G2 is —CH2— or —(C=O)—; R1 and R2 are each independently optionally substituted C12-C36 alkyl, branched and saturated or unsaturated; R3 and R4 are each independently H or optionally substituted C1-C6 alkyl, straight or branched and saturated or unsaturated; R5 is optionally substituted C1-C6 alkyl, straight or branched and saturated or unsaturated; and n is an integer from 2 to 6.
Specified sub-structure embodiment for the compound
The compound of claim 1 is specified with structure (IA), including substituents R6 and R7 where R6 and R7 are each independently H or a C1-C14 alkyl group, with R6 tied to integer a and R7 tied to integer b where a and b range from 1 to 15, and with constraints such that R6/a and R7/b are selected so that R1 and R2 are each independently branched, saturated or unsaturated C12-C36 alkyl groups.
Constrained alkyl size for R1 and R2 (C12-C20 range)
The compound of claim 1 is defined such that R1 and R2 are each independently branched, saturated or unsaturated C12-C20 alkyl groups.
Fixed G1 as hydroxyl (—OH)
The compound of claim 1 is specified to have G1 as —OH.
Amide-like G1 motif (—(C=O)NR5)
The compound described in claim 1 is specified such that G1 is defined as —(C=O)NR5.
Lipid nanoparticle including the compound with a therapeutic agent
A lipid nanoparticle that includes the compound of claim 1 together with a therapeutic agent.
Across the listed independent and dependent scope, the inventive subject matter is centered on the defined structure (I) of a cationic amino lipid with specific options for G1 and G2, constrained alkyl substituent classes for R1-R5, and n restricted to 2-6. The dependent claims shown further narrow the scaffold by fixing or selecting particular G1 forms, narrowing alkyl size ranges for R1 and R2, and extending coverage to lipid nanoparticle formulations that include the compound with a therapeutic agent.
Stated Advantages
Improved intracellular delivery.
Serum protection.
Nucleic acid protection in the lipid nanoparticle.
Serum stability.
Documented Applications
Delivery of nucleic acids, including mRNA, antisense oligonucleotides, miRNA inhibitors, and siRNA, using lipid nanoparticle formulations formed with the defined cationic amino lipids.
Systemic delivery and local delivery using the described lipid nanoparticle formulations.
Therapeutic delivery using lipid nanoparticles comprising a cationic lipid compound of structure (I) and nucleic acids, including antisense and messenger RNA.
In vivo evaluation in mice using luciferase mRNA, with luciferase expression used as an activity readout.
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