Sulfur-Containing Ionizable Lipids for the Delivery of Therapeutic Agents

{
  "publication_number": "US2026102347A1",
  "country": "US",
  "kind": "A1",
  "title": "Sulfur-Containing Ionizable Lipids for the Delivery of Therapeutic Agents",
  "abstract": "Provided are novel sulfur-containing lipids and nanoparticles containing such lipids and a cargo molecule, such as a nucleic acid, methods to formulate said lipids with nucleic acids to produce lipid nanoparticles and chemical routes for making said lipids. The lipids may have the structure of Formula A as defined herein. Formula A",
  "claims": [
    "1. A lipid having a structure of Formula A: or a pharmaceutically acceptable salt thereof; wherein m is 4 to 8; and n is 4 to 8; R 2 and R 3 are independently linear or branched optionally substituted C 3 to C 20 alkyl and optionally comprising 0-2 carbon-carbon double bonds, or are independently unsubstituted, saturated C 6 alkyl; R 1 and R 4 are independently linear or branched optionally substituted C 3 to C 20 alkyl and optionally comprising 0-2 carbon-carbon double bonds; A is either C or N, and if A is C, then W 1 and Y are either bonded to each other or not bonded to each other, and if W 1 and Y are bonded to each other, then W 1 is O or S; W 2 is O or S; X is CH; Y is (CH 2) q, wherein q is 1 or 2; Z is selected from one of structures a-c below, wherein the wavy line represents the bond to X: a. type 2 ionizable head group, wherein the n of the type 2 ionizable head group is 1 to 5; b. type 3 ionizable head group, wherein the m and n of the type 3 ionizable head group are independently 1 to 5; c. type 4 ionizable head group, wherein the m and n of the type 4 ionizable head group are independently 2 to 5 and wherein R=C 1 -C 6 alkyl or cycloalkyl; if W 1 and Y are not bonded to each other, then W 1 is H; W 2 is O, S, NH or NR 2a, wherein R 2a is a C 1 to C 4 alkyl optionally substituted with an OH group; and the moiety of Formula A is a group selected from structures d-h below, wherein the wavy line represents the bond to W 2: d. type 1 ionizable head group, wherein the n of the type 1 ionizable head group is 1 to 5; e. type 5 ionizable head group, wherein the m and n of the type 5 ionizable head group are independently 1 to 5; f. type 6 ionizable head group, wherein the m of the type 6 ionizable head group is 1 to 5 and the n is independently 2 to 5 and wherein the R=C 1 -C 6 alkyl or cycloalkyl; g. (CH 2) n - OH type 7 ionizable head group, wherein the n of the type 7 ionizable head group is 1 to 5; h. type 8 ionizable head group, wherein the n of the type 7 ionizable head group is 1 to 5; i. type 9 ionizable head group, wherein m and n of the type 9 ionizable head group are independently 1 to 5; if A is N, then W 1 and Y are absent; W 2 and X together form a group of structure (CR a R b) p, wherein R a and R b are independently H or C 1 -C 8 alkyl or cycloalkyl, and wherein p is 2 to 6; and Z is OH or NR′R″, wherein R′ and R″ are independently optionally substituted C 1 -C 8 alkyl or cycloalkyl, or wherein R′ and R″ together with the N atom of NR′R″, form an optionally substituted heterocyclic ring that incorporates the N atom to which the R′ and R″ are each bound. 2. The lipid or the pharmaceutically acceptable salt of claim 1, wherein at least one of R 1 and R 4 are, independently, a moiety of Formula B, wherein: Formula B R′ and R″ are, independently, linear or branched optionally substituted C 3 to C 12 alkyl groups and optionally comprising 0-2 carbon-carbon double bonds; R′″ is H or a linear, branched, or cyclic optionally substituted C 1 to C 6 alkyl group; and G 1 and G 2 are, independently, (CR a R b) p, wherein R a and R b are each independently selected from H or optionally substituted C 1 -C 5 alkyl or cycloalkyl, wherein p is 0 to 6. 3. The lipid or the pharmaceutically acceptable salt of claim 1, wherein A is N, W 1 and Y are absent, W 2 and X together form a group of the structure (CR a R b) p, and Z is NR′R″ and wherein the heterocyclic group that incorporates the N atom to which R′ and R″ are bound is pyrrolidine, piperidine or morpholine. 4. The lipid or the pharmaceutically acceptable salt of claim 1, wherein A is a carbon atom. 5. The lipid or the pharmaceutically acceptable salt of claim 4, wherein W 1 and Y are not bonded to each other. 6. The lipid or the pharmaceutically acceptable salt of claim 5, wherein W 2 is O. 7. The lipid or the pharmaceutically acceptable salt of claim 6, wherein the moiety of Formula A is structure d. 8. The lipid or the pharmaceutically acceptable salt of claim 1 having a structure of any one of the following compounds 5-14, 16, 19, 20 and 22-32: 9. A lipid or a pharmaceutically acceptable salt thereof comprising: a protonatable amino head group; two lipophilic chains, wherein the amino head group has a central nitrogen atom or carbon atom to which each of the two lipophilic chains are directly bonded; at least one of the lipophilic chains has the formula: wherein R 1 is a linear or branched optionally substituted C 3 -C 20 alkyl and optionally with varying degrees of unsaturation; wherein R 2 is a linear or branched optionally substituted C 3 -C 20 alkyl and optionally with varying degrees of unsaturation or is an unsubstituted, saturated C 6 alkyl; n is 4 to 8; each lipophilic chain has between 15 and 40 carbon atoms in total; and wherein the lipid is ionizable and has a Clog P of at least 11. 10. The lipid or the pharmaceutically acceptable salt of claim 9 having a structure of any one of the following compounds 15, 17, 18 and 21: 11. The lipid or the pharmaceutically acceptable salt of claim 1, wherein the lipid, when formulated in a lipid nanoparticle comprising an mRNA, results in an increase in biodistribution of the lipid nanoparticle of at least about 10% in the liver and/or one or more extrahepatic tissues relative to a lipid nanoparticle containing DLin-MC3-DMA as measured by luminescence of the mRNA in vivo in the liver and/or one or more extrahepatic tissues. 12. A lipid nanoparticle comprising the lipid of claim 1 and a nucleic acid. 13. The lipid nanoparticle of claim 12, comprising a helper lipid and optionally a hydrophilic polymer-lipid conjugate. 14. The lipid nanoparticle of claim 13, wherein the helper lipid is selected from cholesterol, a diacylglycerol, a glycerophospholipid-cholesterol conjugate and a sphingolipid. 15. A lipid nanoparticle comprising: an ionizable lipid with two lipophilic chains directly bonded to a central nitrogen or carbon atom in which at least one of the lipophilic chains has the formula: n is 4 to 8; wherein the * represent a carbon branch point; wherein R 5 is a linear or branched substituted C 3 -C 30 alkyl group; wherein R 6 is a linear or branched substituted C 3 -C 20 alkyl group or is an unsubstituted, saturated C 6 alkyl; wherein R 5 is substituted with an ester group and R 6 is substituted with a sulfur atom at an alpha, beta or gamma position relative to the carbon branch point; one or more helper lipids; optionally a hydrophilic polymer-lipid conjugate; and a nucleic acid. 16. A method for administering a nucleic acid to a subject in need thereof, the method comprising preparing or providing the lipid nanoparticle of claim 12 comprising the nucleic acid and administering the lipid nanoparticle to the subject. 17. A method for delivering a cargo molecule to a cell, the method comprising contacting the lipid nanoparticle of claim 12 with the cell in vivo or in vitro. 18. The method of claim 17, wherein the cargo molecule is a nucleic acid. 19. (canceled) 20. (canceled) 21. (canceled)"
  ],
  "description_excerpt": "Provided herein are sulfur-containing lipids that may be formulated in a delivery vehicle so as to facilitate the encapsulation of cargo, such as, without limitation, nucleic acids (e.g., RNA or DNA), proteins, peptides, pharmaceutical drugs and salts thereof.\n\nNucleic acid-based therapeutics have enormous potential in medicine. To realize this potential, however, the nucleic acid must be delivered to a target site in a patient. This presents challenges since nucleic acid is rapidly degraded by enzymes in the plasma upon administration. Even if the nucleic acid is delivered to a disease site, there still remains the challenge of intracellular delivery. To address these problems, lipid nanoparticles have been developed that protect nucleic acid from such degradation and facilitate delivery across cellular membranes to gain access to the intracellular compartment, where the relevant translation machinery resides.\n\nA key component of a lipid nanoparticle (LNP) is an ionizable lipid. The ionizable lipid is typically positively charged at low pH, which facilitates association with the negatively charged nucleic acid. However, the ionizable lipid is neutral at physiological pH, making it more biocompatible in biological systems. Further, it has been suggested that after the LNPs are taken up by a cell by endocytosis, the ionizability of these lipids at low pH enables endosomal escape. This in turn enables the nucleic acid to be released into the intracellular compartment.\n\nAn earlier example of an LNP product approved for clinical use and reliant on ionizable lipid is Onpattro®.",
  "cpc": [
    "A61K 9/1272",
    "A61K 31/7105",
    "A61K 9/5123",
    "C07C 2601/14",
    "C07C 323/12",
    "C07C 323/17",
    "C07C 323/25",
    "C07D 317/28",
    "C07D 319/06",
    "C07D 405/06"
  ],
  "ipc": [
    "A61K 31/7105",
    "A61K 9/1272",
    "A61K 9/51",
    "C07C 323/12",
    "C07C 323/17",
    "C07C 323/25",
    "C07D 317/28",
    "C07D 319/06",
    "C07D 405/06"
  ],
  "assignees": [
    "Nanovation Therapeutics Inc"
  ],
  "inventors": [
    "Deaglan Arnold"
  ],
  "filing_date": "2023-09-27",
  "publication_date": "2026-04-16",
  "priority_date": "2022-09-27",
  "application_number": "US-202319115823-A",
  "family_id": "90475021",
  "cited_by_count": 0
}