Lipophilic peptide prodrugs
AssigneeYissum Research Development Company of the Hebrew University of Jerusalem
InventorsAmnon HOFFMAN, Chaim GILON, Joseph FANOUS, Adi KLINGER
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Abstract
The present invention relates to methods of preparing peptide-based prodrugs having enhanced oral bioavailability and intestinal penetration. Said prodrugs are characterized in improved lipophilicity, reduced electric charge and tendency to undergo biotransformation through enzymatic reaction (e.g. in the blood stream) to form biologically active peptides.
Claims20
A process for preparing a peptide-based prodrug, the process comprising:
- (a) providing a peptide;
- and
- (b) reacting said peptide with an alkyl haloformate having the formula XCO2R1, wherein R1 is a primary alkyl and X is a halogen, thereby forming the peptide-based prodrug.
A process for preparing a peptide-based prodrug, the process comprising:
- (a) providing a peptide precursor;
- (b) coupling said peptide precursor with a modified amino acid having a formula selected from the group consisting of:
- wherein
- R1 is a primary alkyl,
- PG is a protecting group;
- wherein the peptide precursor is selected from the group consisting of:
- an amino acid, a peptide and a solid phase resin.
- (c) removing said protecting group PG1 from the product of step (b);
- and
- (d) optionally coupling at least one additional amino acid;
- thereby forming the peptide-based prodrug.
A process for preparing a peptide-based prodrug, the process comprising
- (a) providing a peptide precursor;
- (b) coupling said peptide precursor with a protected amino acid having a formula selected from the group consisting of:
- wherein
- PG1 is a base-labile protecting group;
- PG2 is an acid-labile protecting group;
- n is 3 or 4;
- wherein the peptide precursor is selected from the group consisting of:
- an amino acid, a peptide and a solid phase resin.
- (c) removing said acid-labile protecting group PG2 from the product of step (b) under acidic conditions;
- (d) reacting the product of step (c) with a compound selected from
- wherein R1 is a primary alkyl;
- (e) removing said base-labile protecting group under basic conditions;
- and
- (f) optionally coupling at least one additional amino acid;
- thereby forming the peptide-based prodrug.
Dependencies are inferred from the claim text.