Methods and compositions for lipidization of hydrophilic molecules

{
  "publication_number": "US6225445B1",
  "country": "US",
  "kind": "B1",
  "title": "Methods and compositions for lipidization of hydrophilic molecules",
  "abstract": "Fatty acid derivatives of sulfhydryl-containing compounds (for example, sulfhydryl-containing peptides or proteins) comprising fatty acid-conjugated products with a disulfide linkage are employed for delivery of the compounds to mammalian cells. This modification markedly increases the absorption of the compounds by mammalian cells relative to the rate of absorption of the unconjugated compounds, as well as prolonging blood and tissue retention of the compounds. Moreover, the disulfide linkage in the conjugate is quite labile in the cells and thus facilitates intracellular release of the intact compounds from the fatty acid moieties.",
  "claims": [
    "1. A compound of the formula VI in which P is a therapeutically active protein; R 1 is hydrogen, lower alkyl or aryl; R 2 is selected from the group consisting of a lipid, CH 2 CH 2 CH(NH 2)CO-lipid, - CH 2 CH 2 CH(NHCO-lipid)CO 2 H, or - CH 2 CH 2 CH(NHCO-lipid)CO-lipid, wherein said lipid is a hydrophobic substituent consisting of 4 to 26 carbon atoms and said lipid together with the attached carbonyl is a fatty acid acyl group; and R 3 is - OH.",
    "2. The compound according to claim 1, wherein R 1 is hydrogen and R 2 is a lipid.",
    "3. The compound according to claim 1, wherein R 1 is hydrogen and R 2 is - CH 2 CH 2 CH(NH 2)CO-lipid, - CH 2 CH 2 CH(NHCO-lipid)CO 2 H, or - CH 2 CH 2 CH(NHCO-lipid)CO-lipid.",
    "4. The compound of claim 1, wherein said lipid is a hydrophobic substitutent consisting of 5 to 19 carbon atoms.",
    "5. The compound of claim 1, wherein R 2 together with the attached carbonyl is palmityl, oleyl or stearyl.",
    "6. The compound of claim 1, wherein R 2 together with the attached carbonyl is cholyl or deoxycholyl.",
    "7. A compound of the formula VI in which P is a therapeutically active protein; R 1 is hydrogen, lower alkyl or aryl; R 2 is selected from the group consisting of a lipid, - CH 2 CH 2 CH(NH 2)CO-lipid, - CH 2 CH 2 CH(NHCO-lipid)CO 2 H, or - CH 2 CH 2 CH(NHCO-lipid)CO-lipid; and R 3 is (a) a lipid, - CH 2 CH 2 CH(NH 2)CO-lipid, - CH 2 CH 2 CH(NHCO-lipid)CO 2 H, or - CH 2 CH 2 CH(NHCO-lipid)CO-lipid; or (b) an amino acid chain comprising one or 2 amino acids and terminating in - CO 2 H or - COR 2; wherein said lipid is a hydrophobic substituent consisting of 4 to 26 carbon atoms and said lipid together with the attached carbonyl is a fatty acid acyl group.",
    "8. The compound of claim 7, wherein R 1 is hydrogen.",
    "9. The compound of claim 7, wherein R 1 is hydrogen; R 2 is - CH 2 CH 2 CH(NH 2 CO-lipid, - CH 2 CH 2 CH(NHCO-lipid)CO 2 H, or - CH 2 CH 2 CH(NHCO-lipid)CO-lipid; and R 3 is - NHCH 2 CO 2 H or - NHCH 2 CO-lipid.",
    "10. The compound of claim 7, wherein said lipid group is a hydrophobic substituent consisting of 5 to 19 carbon atoms.",
    "11. The compound of claim 7, wherein R 2 is a lipid group.",
    "12. The compound of claim 7, wherein R 2 together with the attached carbonyl is palmityl, oleyl or stearyl.",
    "13. The compound of claim 7, wherein R 2 together with the attached carbonyl is cholyl or deoxycholyl.",
    "14. The compound of claim 1, wherein P is a protein comprising a thiol containing amino acid.",
    "15. The compound of claim 14, wherein said thiol containing amino acid is cysteine.",
    "16. The compound of claim 7, wherein P is a protein comprising a thiol containing amino acid.",
    "17. The compound of claim 16, wherein said thiol containing amino acid is cysteine."
  ],
  "cpc": [
    "C07D 213/70",
    "A61K 31/44",
    "A61K 38/05",
    "A61K 38/56",
    "A61K 47/54",
    "A61K 47/542",
    "A61K 47/64",
    "C07D 213/71",
    "C07H 19/048",
    "C07H 21/00",
    "C12N 15/111",
    "C12N 2310/3515",
    "C12N 9/0065"
  ],
  "assignees": [
    "UNIV SOUTHERN CALIFORNIA"
  ],
  "filing_date": "1998-07-22",
  "publication_date": "2001-05-01",
  "grant_date": "2001-05-01",
  "priority_date": "1995-01-25",
  "application_number": "US-12011898-A",
  "family_id": "26996314",
  "citations": [
    "EP0482766A1",
    "US5599903A",
    "US5629020A",
    "US5635380A",
    "US5679643A",
    "US5763570A",
    "WO9116067A1"
  ]
}