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US 2015/0087586 A1Published application
Pegylated c-peptide
AssigneeCebix AB
InventorsSheri Barrack, James Callaway, Michelle Mazzoni
Life of this patent
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Abstract
The present invention relates to modified forms of C-peptide, and methods for their use. In one aspect, the modified forms of C-peptide comprise conjugated C-peptide derivatives which exhibit superior pharmacokinetic and biological activity in vivo.
Claims58
A PEGylated C-peptide having a structure selected from the group consisting of structural Formula I and structural Formula II:
- wherein:
- R1=alkyl;
- n1 is 1 to 12;
- n2 is 1 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
18 more elements
A PEGylated C-peptide having structural Formula III:
- wherein:
- R1=alkyl;
- n1 is 1 to 12;
- n3 is 20 to 800;
- Z1, Z2, Z3, and Z4 are independently selected from the group consisting of hydrogen and alkyl;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
19 more elements
A PEGylated C-peptide having structural Formula VI:
- CH3(CH2)7CH═CH(CH2)8—O—(CH2CH2O)n1-[Linker]-[C-peptide] (VI)
- wherein:
- n1 is 20 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
17 more elements
A PEGylated C-peptide having structural Formula VII:
- wherein:
- R1=alkyl;
- n5 is 1 to 12;
- n6 is 20 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
18 more elements
A PEGylated C-peptide having structural Formula VIII:
- wherein:
- R1=alkyl;
- n7 is 1 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
17 more elements
A PEGylated C-peptide having structural Formula IX:
- wherein:
- R1=alkyl;
- n7 is 1 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
17 more elements
A PEGylated C-peptide having a structure selected from the group consisting of structural Formula X and structural Formula XI:
- wherein:
- n9 is 20 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CHOm1—CO—X—,
- —X—(CHOm1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
16 more elements
A PEGylated C-peptide having structural Formula XII:
- wherein:
- R1=alkyl;
- n9 is 20 to 800;
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
17 more elements
A modified C-peptide having the structural Formula XIII:
- Wherein:
- The C-peptide is modified at the N-terminus;
- and
- R2 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, arylalkoxy, aryloxy, heteroaryloxy, alkylamino, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted with a substituent selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
1 more element
A modified C-peptide having the structural Formula XIV:
- [Human Serum Albumin]-[Linker]-[C-peptide] (XIV)
- wherein:
- the linker is selected from the group consisting of:
- -Q1-(CH2)m1—CO—,
- —CO—X—CO—, -Q1-(CH2)m1—X—(CH2)m1—,
- -Q1-(CH2)m1—CO—(CH2)m1—, -Q1-X—CO—X—,
- -Q1-X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- -Q1-X—CO—(CH2)m1—, -Q1-(CH2)m1—CO—X—,
- -Q1-X—(CH2)m1—CO—X—, -Q1-X—CO—(CH2)m1X—,
- -Q1-X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, -Q1-X—(CH2)m1—X—CO—(CH2)m2—,
- -Q1-X—(CH2)m1—CO—X—(CH2)m2—, -Q1-X—(CH2)m1—X—CO—(CH2)m2—X—,
- -Q1-X—(CH2)m1—X—CO—(CH2)m2—CO—,
- -Q1-X—(CH2)m1—CO—X—(CH2)m2—X—, and
- -Q1-X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein Q1 is absent or selected from the group consisting of —CO— or
- each X is independently selected from —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and
- wherein the linker is attached to the N-terminal amino group of C-peptide.
17 more elements
A modified C-peptide having the structural Formula XIII:
- [Hydroxyethyl Starch]-[Linker]-[C-peptide] (XV)
- the linker is selected from the group consisting of:
- —X—, —CO—, —(CH2)m2—,
- —(CH2)m1—CO—, —CO—(CH2)m1—,
- —CO—X—CO—, —(CH2)m1—X—(CH2)m1—,
- —(CH2)m1—CO—(CH2)m1—, —X—CO—X—,
- —X—(CH2)m1—X—, —CO—(CH2)m1—CO—,
- —X—CO—(CH2)m1—, —(CH2)m1—CO—X—,
- —X—(CH2)m1—CO—X—, —X—CO—(CH2)m1 X—,
- —X—CO—(CH2)m1—CO—X—(CH2)m1—X—CO—, —X—(CH2)m1—X—CO—(CH2)m2—,
- —X—(CH2)m1—CO—X—(CH2)m2—, —X—(CH2)m1—X—CO—(CH2)m2—X—,
- —X—(CH2)m1—X—CO—(CH2)m2—CO—,
- —X—(CH2)m1—CO—X—(CH2)m2—X—, and
- —X—(CH2)m1—CO—X—(CH2)m2—CO—;
- wherein each X is independently selected from —O—NH—, —NH—NH—, —O—, —S—, or NH— or is missing;
- each m1 is independently 0 to 5;
- each m2 is independently 1 to 5;
- and wherein the linker is attached to the N-terminal amino group of C-peptide.
15 more elements
Dependencies are inferred from the claim text.