Methods and compositions for lipidization of hydrophilic molecules

{
  "publication_number": "US5936092A",
  "country": "US",
  "kind": "A",
  "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 general formula V A--S--S--CH.sub.2 --CR.sup.1 (NHCOR.sup.2)C(═O)R.sup.3 V in which A is an aromatic activating residue selected from the group consisting of 2-pyridyl, 4-nitrophenyl and 5-(2-nitro)benzoic acid; R 1 is hydrogen, lower alkyl or aryl; R 2 is hydrophobic substituent consisting of 4 to 26 carbon atoms, wherein R 2 together with the attached carbonyl is a fatty acid acyl group; and R 3 is --OH, R 2 or an amino acid chain comprising one or 2 amino acids and terminating in --CO 2 H or --COR 2.",
    "2. A compound according to claim 1, wherein R 1 is hydrogen R 2 is a hydrophobic group and R 3 is --OH.",
    "3. A compound of general formula III A--S--S--CH.sub.2 --CR.sup.1 (NH.sub.2)C(═O)R.sup.3 ' III in which R 3 ' is --OH or an amino acid chain comprising one or two amino acids and terminating in --CO 2 H; A is an aromatic activating residue selected from the group consisting of 2-pyridyl, 4-nitrophenyl and 5-(2-nitro)benzoic acid; and R 1 is lower alkyl or aryl.",
    "4. A compound according to claim 3, wherein R 3 ' is --OH.",
    "5. A compound according to claim 3, wherein R 3 ' is --NHCH 2 CO 2 H.",
    "6. The compound of claim 1, wherein R 2 together with the attached carbonyl is palmityl, oleyl or stearyl.",
    "7. A compound of general formula V A--S--S--CH.sub.2 --CR.sup.1 (NHCOR.sup.2)C(═O)R.sup.3 V in which A is an aromatic activating residue selected from the group consisting of 2-pyridyl, 4-nitrophenyl and 5-(2-nitro)benzoic acid; R 1 is hydrogen, lower alkyl or aryl; R 2 is --CH 2 CH 2 CH(NH 2)CO 2 H or --CH 2 CH 2 CH(NHCOR)COR 4; R 3 is --NHCH 2 CO 2 H or --NHCH 2 COR 4; R 4 is a hydrophobic substituent consisting of 4 to 26 carbon atoms, wherein R 4 together with the attached carbonyl is a fatty acid acyl group; with the proviso that at least one of R 2 and R 3 comprises an R 4 group.",
    "8. The compound of claim 7, wherein R 1 is hydrogen.",
    "9. A compound of general formula V A--S--S--CH.sub.2 --CR.sup.1 (NHCOR.sup.2)C(═O)R.sup.3 V in which A is an aromatic activating residue selected from the group consisting of 2-pyridyl, 4-nitrophenyl and 5-(2-nitro)benzoic acid; R 1 is hydrogen, lower alkyl or aryl; R 2 together with the attached carbonyl is cholyl or deoxycholyl; and R 3 is --OH, R 2 or an amino acid chain comprising one or 2 amino acids and terminating in --CO 2 H or --COR 2."
  ],
  "description_excerpt": "This application is a division of application Ser. No. 08/524,362 filed on Sep. 5, 1995 which application is now pending, and which is a continuation-in-part of application Ser. No. 08/349,717 filed Jan. 25, 1995, which application is now abandoned.\n\nThe present invention relates generally to the fields of biology and medicine. More particularly, the present invention is directed to methods and compositions useful in increasing in mammals the absorption and retention of hydrophilic molecules, in particular peptides and proteins.\n\nAdvances in biotechnology have made possible the production of large amounts of therapeutically active and pure proteins and peptides. Currently, the therapeutic effects of most of these agents can be achieved only when they administered via invasive routes, such as by injection. Since most proteins have very short half lives, effective concentrations of these agents can be maintained only when administered by frequent injections.\n\nAlthough the administration of proteins by injection is the most effective means of their delivery in vivo, patient tolerance of multiple injections is very poor. In addition, the administration of drugs via the injection routes is a skilled job and requires training; this skill and training may not always be transferable to patients. In cases where protein drugs have a life-saving role, the administration by the injection route can be accepted by the patients. However, in cases where protein drugs are just one of several possible therapies, injections of proteins and peptides are unlikely to be accepted by the patients.",
  "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"
  ],
  "ipc": [
    "A61K 31/70",
    "A61K 38/00",
    "A61K 38/17",
    "A61K 47/48",
    "C07C 323/58",
    "C07D 213/70",
    "C07D 213/71",
    "C07H 21/00",
    "C07K 1/113",
    "C07K 14/47",
    "C12N 9/02",
    "C12N 9/08"
  ],
  "assignees": [
    "University of Southern California USC"
  ],
  "inventors": [
    "Wei-Chiang Shen",
    "Hossein M. Ekrami"
  ],
  "filing_date": "1996-11-01",
  "publication_date": "1999-08-10",
  "grant_date": "1999-08-10",
  "priority_date": "1995-01-25",
  "application_number": "US-74235796-A",
  "family_id": "26996314",
  "cited_by_count": 64,
  "citations": [
    "US5679643A",
    "US5763570A",
    "WO1991016067A1",
    "EP0482766A1",
    "US5599903A"
  ]
}