EGF(A) analogues with fatty acid substituents

Patent metadata

Field	Value
Publication number	US-10822385-B2
Application number	US-201716069932-A
Country	US
Kind code	B2
Filing date	Jan 13, 2017
Priority date	Jan 13, 2016
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The invention relates to compounds derived from the EGF(A) domain of LDL-R, in particular compounds comprising a peptide analogue of the wild-type EGF(A) (LDL-R(293-332)) sequence and at least one substituent comprising at least one fatty acid group. The invention also relates to a pharmaceutical composition thereof and use a medicament. The novel EGF(A) compounds of the invention are useful as treatment e.g. in the field of cholesterol lowering, dyslipidaemia and cardiovascular disease.

First claim

The invention claimed is:

1. An EGF(A) derivative comprising 1) an EGF(A) peptide analogue of SEQ ID NO: 1 comprising amino acid 301Leu, an amino acid substitution of 312Lys and up to six additional amino acid substitutions, wherein SEQ ID NO: 1 corresponds to amino acids 293-332 of the EGF(A) domain of the LDL-R, and 2) a substituent comprising at least one fatty acid group, wherein the substituent is attached to the EGF(A) peptide analogue.

2. The EGF(A) derivative according to claim 1 , wherein said substituent comprises a functional group, wherein said functional group is a carboxylic acid, a sulphonic acid, a tetrazole moiety, a methylsulfonylcarbamoylamino moiety or a 3-hydroxy-isoxazole moiety and further comprises 8-20 consecutive —CH 2 — groups, wherein said substituent is attached to a lysine residue or the N-terminal residue of said EGF(A) peptide analogue.

3. The EGF(A) derivative according to claim 1 , wherein said substituent has Formula I:
Z 1 —Z 2 —Z 3 —Z 4 —Z 5 —Z 6 —Z 7 —Z 8 —Z 9 —Z 10 —  [I] wherein

Z 1 is selected from:
Chem. 1: HOOC—(CH 2 ) n —CO—*,
Chem. 2: tetrazolyl-(CH 2 ) n —CO—*,
Chem. 3: HOOC—(C 6 H 4 )—O—(CH 2 ) m —CO—*,
Chem. 4: HOS(O) 2 —(CH 2 ) n —CO—*,
Chem. 5: MeS(O) 2 NH(CO)N—(CH 2 ) n —CO—* and
Chem. 6: 3-HO-Isoxazole-(CH 2 ) n —CO—*
wherein
n is an integer in the range of 8-20,
m is an integer in the range of 8-11,
the —COOH group in Chem. 3 can be attached to position 2, 3 or 4 on the phenyl ring, the symbol * indicates the attachment point to the nitrogen in Z 2 or, if Z 2 is a bond, to the nitrogen on the neighbouring Z element; or if Z 3 -Z 10 are all bonds, to a lysine residue or the N-terminal residue of said EGF(A) peptide analogue;
Z 2 is selected from
Chem. 7: —NH—SO 2 —(CH 2 ) 3 —CO—*,
Chem. 8: —NH—CH 2 —(C 6 H 10 )—CO—* and
a bond; and the symbol * indicates the attachment point to Z 3 or, if Z 3 is a bond, to the neighbouring Z element, or if Z 4 -Z 10 are all bonds, to a lysine residue or the N-terminal residue of said EGF(A) peptide analogue;
Z 3 is selected from:
γGlu, Glu and a bond;
Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 are selected, independently of each other, from:
Glu, γGlu, Gly, Ser, Ala, Thr, Ado, Aeep, Aeeep, TtdSuc and a bond; and
Z 10 is selected from:
Chem. 14: —NH—CH 2 —(C 6 H 4 )—CH 2 —* and a bond, and wherein the symbol * indicates the attachment point to a lysine residue or the N-terminal residue of said EGF(A) peptide analogue.

4. The EGF(A) derivative according to claim 1 , wherein the EGF(A) derivative comprises one or two substituent(s) selected from the group consisting of:
HOOC—(CH 2 ) 18 —CO-gGlu-2×ADO—
HOOC—(CH 2 ) 18 —CO—NH—CH 2 —(C 6 H 10 )—CO-gGlu-2×ADO—
HOOC—(CH 2 ) 16 —CO-gGlu-2×ADO—
HOOC—(CH 2 ) 16 —CO-gGlu-2×ADO—NH—CH 2 —(C 6 H 4 )—CH 2 —
HOOC—(CH 2 ) 16 —CO-gGlu-
HOOC—(CH 2 ) 16 —CO—NH—CH 2 —(C 6 H 10 )—CO-gGlu-2×ADO—
HOOC—(CH 2 ) 14 —CO-gGlu-2×ADO—
HOOC—(CH 2 ) 14 —CO-gGlu-
HOOC—(CH 2 ) 14 —CO-gGlu-2×ADO—
HOOC—(CH 2 ) 12 —CO-gGlu-2×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-2×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-3×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-2×gGlu-
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-3×Gly-
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-2×gGlu-2×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-TtdSuc-
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 9 —CO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-4×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO—NH—CH 2 —(C 6 H 10 )—CO-gGlu-2×ADO—
4-HOOC—(C 6 H 4 )—O—(CH 2 ) 9 —CO-gGlu-2×ADO—
3-HOOC—(C 6 H 4 )—O—(CH 2 ) 9 —CO-gGlu-2×ADO—
3-HO-Isoxazole-(CH 2 ) 12 —CO-gGlu-2×ADO—
HOS(O) 2 —(CH 2 ) 15 —CO-gGlu-2×ADO—NH—CH 2 —(C 6 H 4 )—CH 2 —
HOS(O) 2 —(CH 2 ) 13 —CO-gGlu-2×ADO—
Tetrazolyl-(CH 2 ) 15 —CO—NH—SO 2 —(CH 2 ) 3 —CO-ADO-ADO—NH—CH 2 —(C 6 H 4 )—CH 2 —
Tetrazolyl-(CH 2 ) 12 —CO-gGlu-2×ADO—
Tetrazolyl-(CH 2 ) 15 —CO-gGlu-2×ADO- and
MeS(O) 2 NH(CO)NH—(CH 2 ) 12 —CO-gGlu-2×ADO-.

5. The EGF(A) derivative according to claim 4 , wherein amino acid residue(s): 295Asn, 296Glu, 298Leu, 302Gly and/or 310Asp of the EGF(A) peptide analogue are not substituted.

6. The EGF(A) derivative according to claim 4 , wherein said EGF(A) peptide analogue further comprises one or two Lys residue(s) selected from the group consisting of: 292Lys, 293Lys, 294Lys, 296Lys, 299Lys, 300Lys, 303Lys, 305Lys, 306Lys, 309Lys, 311Lys, 313Lys, 314Lys, 315Lys, 316Lys, 318Lys, 320Lys, 321Lys, 322Lys, 323Lys, 324Lys, 325Lys, 326Lys, 327Lys, 328Lys, 329Lys, 330Lys, 332Lys and 333Lys, wherein 292Lys represents adding a Lys residue to the N-terminus of SEQ ID NO: 1 and 333Lys represents adding a Lys residue to the C-terminus of SEQ ID NO: 1, and wherein said one or two substituent(s) is attached to said one or two Lys residue(s) in said EGF(A) peptide analogue.

7. The EGF(A) derivative according to claim 4 , wherein amino acids 297Cys, 304Cys, 308Cys, 317Cys, 319Cys and 331Cys of the EGF(A) peptide analogue are not substituted.

8. The EGF(A) derivative according to claim 4 , wherein said EGF(A) peptide analogue further comprises two Lys residues selected from the pairs consisting of:
i. 293K and 294K
ii. 293K and 333K
iii. 309K and 313K
iv. 309K and 324K
v. 309K and 328K
vi. 309K and 332K
vii. 309K and 333K
viii. 311K and 313K
ix. 311K and 313K
x. 313K and 321K
xi. 313K and 324K
xii. 313K and 328K
xiii. 313K and 332K
xiv. 313K and 333K
xv. 314K and 333K
xvi. 321K and 332K
xvii. 321K and 333K
xviii. 321K and 333K
xix. 324K and 328K
xx. 328K and 333K
xxi. 330K and 333K and
xxii. 332K and 333K,

wherein 333K represents adding a Lys residue to the C-terminus of SEQ ID NO: 1.

9. The EGF(A) derivative according to claim 4 , wherein said EGF(A) peptide analogue comprises one or two Lys residue(s) selected from the group consisting of: 313Lys, 324Lys, 328Lys, and 333Lys and one or two substituent(s) is attached to said one or two Lys residue(s) in said EGF(A) peptide analogue, wherein 333Lys represents adding a Lys residue to the C-terminus of SEQ ID NO: 1.

10. The EGF(A) derivative according to claim 1 , wherein amino acids 295Asn, 296Glu, 298Leu, 302Gly and/or 310Asp of the EGF(A) peptide are not substituted.

11. The EGF(A) derivative according to claim 1 , wherein amino acid 310Asp of the EGF(A) peptide is not substituted.

12. The EGF(A) derivative according to claim 1 , wherein amino acid 295Asn of the EGF(A) peptide is not substituted.

13. The EGF(A) derivative according to claim 1 , wherein said EGF(A) peptide analogue further comprises one or two Lys residue(s) selected from the group consisting of: 292Lys, 293Lys, 294Lys, 296Lys, 299Lys, 300Lys, 303Lys, 305Lys, 306Lys, 309Lys, 311Lys, 313Lys, 314Lys, 315Lys, 316Lys, 318Lys, 320Lys, 321Lys, 322Lys, 323Lys, 324Lys, 325Lys, 326Lys, 327Lys, 328Lys, 329Lys, 330Lys, 332Lys and 333Lys, wherein 292Lys represents adding a Lys residue to the N-terminus of SEQ ID NO: 1 and 333Lys represents adding a Lys residue to the C-terminus of SEQ ID NO: 1, and wherein said substituent is attached to said one or two Lys residue(s) in said EGF(A) peptide analogue.

14. The EGF(A) derivative according to claim 1 , wherein amino acid 310Asp is not substituted and 312Lys is substituted by Glu, Asp, Gln or Arg.

15. The EGF(A) derivative according to claim 1 , wherein amino acid 310Asp is not substituted and 299Asp is not substituted to Glu, Val or His.

16. The EGF(A) derivative according to claim 15 , wherein amino acids 295Asn, 296Glu, 298Leu, and/or 302Gly of the EGF(A) peptide analogue are not substituted.

17. The

Assignees

• Novo Nordisk As

Inventors

• Chen Jianhe
• Lau Jesper F
• Kodra Janos Tibor
• Wieczorek Birgit
• Linderoth Lars
• Thoegersen Henning
• Rasmussen Salka Elboel
• Garibay Patrick William

Classifications

• C07K14/705 Primary

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• C07K14/485 Primary

  Epidermal growth factor [EGF], i.e. urogastrone · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title