Egf(a) analogues with fatty acid substituents

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.

1 . An EGF(A) derivative comprising an EGF(A) peptide analogue of the EGF(A) domain of LDL-R defined by SEQ ID NO: 1, comprising 301Leu and a substituent comprising at least one fatty acid group. 
     
     
         2 . The EGF(A) derivative according to  claim 1 , wherein said substituent comprises a carboxylic acid, a sulphonic acid, a tetrazole moiety, a methylsulfonylcarbamoylamino moiety or a 3-hydroxy-isoxazole moiety and 8-20 consecutive —CH 2 — groups. 
     
     
         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:
   HOOC—(CH 2 ) n —CO—*,  Chem. 1:
 
   tetrazolyl-(CH 2 ) n —CO—*,  Chem. 2:
 
   HOOC—(C 6 H 4 )—O—(CH 2 ) m —CO—*,  Chem. 3:
 
   HOS(O) 2 —(CH 2 ) n —CO—*,  Chem. 4:
 
   MeS(O) 2 NH(CO)N—(CH 2 ) n —CO—* and  Chem. 5:
 
   3-HO-Isoxazole-(CH 2 ) n —CO—*  Chem. 6:
 
    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;   Z 2  is selected from
   *—NH—SO 2 —(CH 2 ) 3 —CO—*,  Chem. 7:
 
   *—NH—CH 2 —(C 6 H 10 )—CO—* and  Chem. 8:
 
    a bond;   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:
   *—NH—CH 2 —(C 6 H 4 )—CH 2 —* and a bond.  Chem. 14:
 
   
     
     
         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-2xADO-   HOOC—(CH 2 ) 18 —CO—NH—CH 2 —(C 6 H 10 )—CO-gGlu-2xADO-   HOOC—(CH 2 ) 16 —CO-gGlu-2xADO-   HOOC—(CH 2 ) 16 —CO-gGlu-2xADO—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-2xADO-   HOOC—(CH 2 ) 14 —CO-gGlu-2xADO-   HOOC—(CH 2 ) 14 —CO-gGlu-   HOOC—(CH 2 ) 14 —CO-gGlu-2xADO-   HOOC—(CH 2 ) 12 —CO-gGlu-2xADO-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-2xADO-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-3xADO-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO—2xgGlu-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO-gGlu-3xGly-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO—2xgGlu-2xADO-   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-4xADO-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 10 —CO—NH—CH 2 —(C 6 H 10 )—CO-gGlu-2xADO-   4-HOOC—(C 6 H 4 )—O—(CH 2 ) 9 —CO-gGlu-2xADO-   3-HOOC—(C 6 H 4 )—O—(CH 2 ) 9 —CO-gGlu-2xADO-   3-HO-Isoxazole-(CH 2 ) 12 —CO-gGlu-2xADO-   HOS(O) 2 —(CH 2 ) 15 —CO-gGlu-2xADO—NH—CH 2 —(C 6 H 4 )—CH 2 —   HOS(O) 2 —(CH 2 ) 13 —CO-gGlu-2xADO-   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-2xADO-   Tetrazolyl-(CH 2 ) 15 —CO-gGlu-2xADO- and   MeS(O) 2 NH(CO)NH—(CH 2 ) 12 —CO-gGlu-2xADO—.   
     
     
         5 . The EGF(A) derivative according to  claim 1 , wherein the EGF(A) peptide analogue comprises one, two, three, four or all five of the following (wild type) amino acid residue(s): 295Asn, 296Glu, 298Leu, 302Gly and 310Asp. 
     
     
         6 . The EGF(A) derivative according to  claim 1 , wherein the EGF(A) peptide analogue comprises the wild-type residue 310Asp. 
     
     
         7 . The EGF(A) derivative according to  claim 1 , wherein the EGF(A) peptide analogue comprises the wild-type residue 295Asn. 
     
     
         8 . The EGF(A) derivative according to  claim 1 , wherein at least one substituent is attached to a Lys residue in the EGF(A) peptide analogue selected from the group consisting of: 292Lys, 293Lys, 294Lys, 296Lys, 299Lys, 300Lys, 303Lys, 305Lys, 306Lys, 309Lys, 311Lys, 312Lys, 313Lys, 314Lys, 315Lys, 316Lys, 318Lys, 320Lys, 321Lys, 322Lys, 323Lys, 324Lys, 325Lys, 326Lys, 327Lys, 328Lys, 329Lys, 330Lys, 332Lys and 333Lys. 
     
     
         9 . The EGF(A) derivative according to  claim 1 , wherein the EGF(A) derivative is selected from the group of EGF(A) derivatives consisting of: Example compounds 1-44, 46-47, 51-55, 57, 60-64, 66-69, 71-102 and 106-159. 
     
     
         10 . An EGF(A) peptide analogue of the EGF(A) domain of LDL-R defined by SEQ ID NO: 1, wherein the EGF(A) peptide analogue comprises 301Leu, 310Asp and an amino acid substitution of 312Lys. 
     
     
         11 . An EGF(A) peptide analogue of the EGF(A) domain defined by SEQ ID NO: 1, wherein the EGF(A) peptide analogue comprises 301Leu and 310Asp and wherein the peptide does not have a substitution of 299Asp to Glu, Val or His. 
     
     
         12 . The EGF(A) peptide analogue according to  claim 10 , wherein the EGF(A) peptide analogue comprises Cys residues 297Cys, 304Cys, 308Cys, 317Cys, 319Cys and 331Cys. 
     
     
         13 . The EGF(A) peptide analogue according to  claim 10 , further comprising one, two, three, four or all five of the following (wild type) amino acid residue(s): 295Asn, 296Glu, 298Leu, 302Gly and 310Asp. 
     
     
         14 . The EGF(A) peptide analogue according to  claim 10 , EGF(A) further comprising at least one Lys substitution 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. 
     
     
         15 . The EGF(A) peptide analogue according to  claim 10 , wherein said peptide sequence is selected from the group consisting of: SEQ ID NOs: 2-47 and 49-106. 
     
     
         16 . The EGF(A) peptide analogue according to  claim 11 , wherein the EGF(A) peptide analogue comprises Cys residues 297Cys, 304Cys, 308Cys, 317Cys, 319Cys and 331Cys. 
     
     
         17 . The EGF(A) peptide analogue according to  claim 11 , further comprising one, two, three, four or all five of the following (wild type) amino acid residue(s): 295Asn, 296Glu, 298Leu, 302Gly and 310Asp. 
     
     
         18 . The EGF(A) peptide analogue according to  claim 11 , EGF(A) further comprising at least one Lys substitution 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. 
     
     
         19 . The EGF(A) peptide analogue according to  claim 12 , further comprising one, two, three, four or all five of the following (wild type) amino acid residue(s): 295Asn, 296Glu, 298Leu, 302Gly and 310Asp. 
     
     
         20 . The EGF(A) peptide analogue according to  claim 12 , EGF(A) further comprising at least one Lys substitution 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.