US2008058270A1PendingUtilityA1
Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
Est. expirySep 29, 2017(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/00A61P 9/10A61P 3/06A61P 3/04A61P 31/04A61P 3/00A61K 38/10A61K 38/16C07K 14/775A61K 38/00
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Claims
Abstract
The present invention provides peptides and peptide analogues that mimic the structural and pharmacological properties of human ApoA-I. The peptides and peptide analogues are useful to treat a variety of disorders associated with dyslipidemia.
Claims
exact text as granted — not AI-modified1 . An ApoA-I agonist comprising:
(i) a 14 to 22-residue peptide or peptide analogue which forms an amphipathic α-helix in the presence of lipids and which comprises the structural formula (I): Z 1 -X 1 —X 2 —X 3 —X 4 —X 5 —X 6 —X 7 —X 8 —X 9 —X 10 —X 11 —X 12 —X 13 —X 14 —X 15 —X 16 —X 17 —X 18 X 1 is Pro (P), Ala (A), Gly (G), Asn (N), Gln (Q) or D-Pro (p); X 2 is an aliphatic amino acid; X 3 is Leu (L); X 4 is an acidic amino acid; X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 7 is a basic amino acid; X 8 is an acidic amino acid; X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 11 is an acidic amino acid or Asn (N); X 12 is an acidic amino acid; X 13 is Leu (L), Trp (W) or Phe (F); X 14 is a basic amino acid or Leu (L); X 15 is Gln (Q) or Asn (N); X 16 is a basic amino acid; X 17 is Leu (L); X 18 is a basic amino acid; Z 1 is H 2 N— or RC(O)NH—; Z 2 is —C(O)NRR, —C(O)OR or —C(O)OH or a salt thereof; each R is independently —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 5 -C 20 ) aryl, (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl or a 1 to 4-residue peptide or peptide analogue; each “—” between residues X n independently designates an amide linkage, a substituted amide linkage, an isostere of an amide or an amide mimetic; or (ii) a deleted from of structural formula (I) in which at least one and up to eight of residues X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are deleted; or (iii) an altered form of structural formula (I) in which at least one of residues X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 or X 18 is conservatively substituted with another residue.
2 . The ApoA-I agonist of claim 1 which exhibits at least about 38% LCAT-activation activity as compared with human ApoA-I.
3 . The ApoA-I agonist of claim 1 which is the altered form of structural formula (I).
4 . The ApoA-I agonist of claim 3 in which the hydrophobic residues are fixed according to structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue.
5 . The ApoA-I agonist of claim 4 in which:
X 1 is Pro (P), D-Pro (p), Gly (G), Asn (N) or Ala (A); X 2 is Ala (A), Leu (L) or Val (V); X 3 is Leu (L); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 13 is Leu (L), Trp (W) or Phe (F); X 17 is Leu (L); and at least one of X 4 , X 7 , X 8 , X 11 , X 12 , X 14 , X 15 , X 16 and X 18 is conservatively substituted with another residue.
6 . The ApoA-I agonist of claim 3 in which the hydrophilic residues are fixed according to structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue.
7 . The ApoA-I agonist of claim 6 in which:
X 4 is Asp (D) or Glu (E); X 7 is Arg (R), Lys (K) or Orn; X 8 is Asp (D) or Glu (E); X 11 is Asn (N) or Glu (E); X 12 is Glu (E); X 14 is Lys (K), Arg (R) or Orn; X 15 is Gln (Q) or Asn (N); X 16 is Lys (K), Arg (R) or Orn; X 18 is Asn (N) or Gln (Q); and at least one of X 1 , X 2 , X 3 , X 5 , X 6 , X 9 , X 10 , X 13 and X 17 is conservatively substituted with another residue.
8 . The ApoA-I agonist of claim 6 in which X 3 is Leu (L), X 6 is Phe (F), X 9 is Leu (L) or Trp (W), X 10 is Leu (L) or Trp (W) and at least one of X 1 , X 2 , X 5 , X 13 and X 17 is conservatively substituted with another residue.
9 . The ApoA-I agonist of claim 5 or 7 in which the substituting residue is classified within the same sub-category as the substituted residue.
10 . The ApoA-I agonist of claim 1 which is the deleted form of structural formula (I).
11 . The ApoA-I agonist of claim 10 in which one helical turn of the peptide or peptide analogue is deleted.
12 . The ApoA-I agonist of claim 1 which is an 18-residue peptide or peptide analogue of structural formula (I).
13 . The ApoA-I agonist of claim 12 in which:
the “—” between residues designates —C(O)NH—; Z 1 is H 2 N—; and Z 2 is —C(O)OH or a salt thereof.
14 . The ApoA-I agonist of claim 13 , in which:
X 1 is Pro (P), Ala (A), Gly (G), Asn (N) or D-Pro (p); X 2 is Ala (A), Val (V) or Leu (L); X 3 is Leu (L); X 4 is Asp (D) or Glu (E); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 7 is Arg (R), Lys (K) or Orn; X 8 is Asp (D) or Glu (E); X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 11 is Glu (E) or Asn (N); X 12 is Glu (E); X 13 is Leu (L), Trp (W) or Phe (F); X 14 is Arg (R), Lys (K) or Orn; X 15 is Gln (Q) or Asn (N); X 16 is Arg (R), Lys (K) or Orn; X 17 is Leu (L); and X 18 is Arg (R), Lys (K) or Orn.
15 . The ApoA-I agonist of claim 1 which is selected from the group consisting of:
peptide 191
PVLDLLRELLEELKQKLK*;
(SEQ ID NO:191)
peptide 192
PVLDLFKELLEELKQKLK*;
(SEQ ID NO:192)
peptide 193
PVLDLFRELLEELKQKLK*;
(SEQ ID NO:193)
peptide 194
PVLELFRELLEELKQKLK*;
(SEQ ID NO:194)
peptide 195
PVLELFKELLEELKQKLK*;
(SEQ ID NO:195)
peptide 196
PVLDLFRELLEELKNKLK*;
(SEQ ID NO:196)
peptide 197
PLLDLFRELLEELKQKLK*;
(SEQ ID NO:197)
peptide 198
GVLDLFRELLEELKQKLK*;
(SEQ ID NO:198)
peptide 199
PVLDLFRELWEELKQKLK*;
(SEQ ID NO:199)
peptide 200
NVLDLFRELLEELKQKLK*;
(SEQ ID NO:200)
peptide 201
PLLDLFKELLEELKQKLK*;
(SEQ ID NO:201)
peptide 202
PALELFKDLLEELRQKLR*;
(SEQ ID NO:202)
peptide 203
AVLDLFRELLEELKQKLK*;
(SEQ ID NO:203)
peptide 204
PVLDFFRELLEELKQKLK*;
(SEQ ID NO:204)
peptide 205
PVLDLFREWLEELKQKLK*;
(SEQ ID NO:205)
peptide 206
PLLELLKELLEELKQKLK*;
(SEQ ID NO:206)
peptide 207
PVLELLKELLEELKQKLK*;
(SEQ ID NO:207)
peptide 208
PALELFKDLLEELRQRLK*;
(SEQ ID NO:208)
peptide 209
PVLDLFRELLNELLQKLK;
(SEQ ID NO:209)
peptide 210
PVLDLFRELLEELKQKLK;
(SEQ ID NO:210)
peptide 211
PVLDLFRELLEELOQOLO*;
(SEQ ID NO:211)
peptide 212
PVLDLFOELLEELOQOLK*;
(SEQ ID NO:212)
peptide 213
PALELFKDLLEEFRQRLK*;
(SEQ ID NO:213)
peptide 214
pVLDLFRELLEELKQKLK*;
(SEQ ID NO:214)
peptide 215
PVLDLFRELLEEWKQKLK*;
(SEQ ID NO:215)
peptide 229
PVLELFERLLEDLQKKLK;
(SEQ ID NO:229)
peptide 230
PVLDLFRELLEKLEQKLK;
(SEQ ID NO:230)
peptide 231
PLLELFKELLEELKQKLK*;
(SEQ ID NO:231)
in either the N- and/or C-terminal blocked or unblocked forms.
16 . A multimeric ApoA-I agonist which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has the structural formula (II):
HH LL m -HH n LL m -HH (II) or a pharmaceutically acceptable salt thereof, wherein:
each m is independently an integer from 0 to 1;
n is an integer from 0 to 10;
each “HH” is independently a peptide or peptide analogue according to claim 1;
each I“LL” is independently a bifunctional linker; and
each “-” independently designates a covalent linkage.
17 . A multimeric ApoA-I agonist which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has the structural formula (III):
X—N ya —X (ya-1) N yb —X (yb-1) ) p (III)
or a pharmaceutically acceptable salt thereof, wherein:
each X is independently HH LL m -HH n LL m -HH;
each HH is independently a core peptide of structure (I) or an analogue or mutated, truncated, internally deleted or extended form thereof as described herein;
each LL is independently a bifunctional linker;
each m is independently an integer from 0 to 1;
each n is independently an integer from 0 to 8;
N ya and N yb are each independently a multifunctional linking moiety where y a and y b represent the number of functional groups on N ya and N yb , respectively;
each y a or y b is independently an integer from 3 to 8;
p is an integer from 0 to 7; and
each “-” independently designates a covalent bond.
18 . A multimeric ApoA-I agonist which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has the structural formula (IV) or (V):
or a pharmaceutically acceptable salt thereof, wherein:
each X is independently HH LL m -HH n LL m -HH;
each HH is independently a peptide or peptide analogue according to claim 1;
each LL is independently a bifunctional linker;
each n is independently an integer from 0 to 1;
each m is independently an integer from 0 to 8;
R 1 is —OR or —NRR; and
each R is independently —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl; (C 5 -C 20 ) aryl (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl.
19 . The multimeric ApoA-I agonist of claim 16 , 17 or 18 in which the bifunctional linker is cleavable.
20 . The ApoA-I multimeric agonist of claim 16 , 17 or 18 in which n is 0.
21 . The multimeric ApoA-I agonist of claim 20 in which m is 0.
22 . The multimeric ApoA-I agonist of claim 16 , 17 or 18 in which each HH is independently a peptide according to claim 13 .
23 . The multimeric ApoA-I agonist of claim 16 , 17 or 18 in which each HH is independently a peptide according to claim 14 .
24 . The multimeric ApoA-I agonist of claim 16 , 17 or 18 in which each HH is independently a peptide according to claim 15 .
25 . An ApoA-I agonist-lipid complex comprising an ApoA-I agonist and a lipid, wherein the ApoA-I agonist is a peptide or peptide analogue according to claim 1 , a multimeric ApoA-I agonist according to claim 16 , a multimeric ApoA-I agonist according to claim 17 , or a multimeric ApoA-I agonist according to claim 18 .
26 . The ApoA-I agonist-lipid complex of claim 25 in which the ApoA-I agonist is a peptide according to claim 12 .
27 . The ApoA-I agonist-lipid complex of claim 25 in which the ApoA-I agonist is a peptide according to claim 13 .
28 . The ApoA-I agonist-lipid complex of claim 25 in which the ApoA-I agonist is a peptide according to claim 14 .
29 . The ApoA-I agonist-lipid complex of claim 25 in which the ApoA-I agonist is a peptide according to claim 15 .
30 . The ApoA-I agonist-lipid complex of claim 25 in which the lipid is sphingomyelin.
31 . The ApoA-I agonist-lipid complex of claim 25 which is in the form of a lyophilized powder.
32 . The ApoA-I agonist-lipid complex of claim 25 which is in the form of a solution.
33 . A pharmaceutical composition comprising an ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the ApoA-I agonist is a peptide or peptide analogue according to claim 1 , a multimeric ApoA-I agonist according to claim 16 , a multimeric ApoA-I agonist according to claim 17 , or a multimeric ApoA-I agonist according to claim 18 .
34 . The pharmaceutical composition of claim 33 in which the ApoA-I agonist is a peptide according to claim 12 .
35 . The pharmaceutical composition of claim 33 in which the ApoA-I agonist is a peptide according to claim 13 .
36 . The pharmaceutical composition of claim 33 in which the ApoA-I agonist is a peptide according to claim 14 .
37 . The pharmaceutical composition of claim 33 in which the ApoA-I agonist is a peptide according to claim 15 .
38 . The pharmaceutical composition of claim 33 , 34 , 35 , 36 or 37 , in which the ApoA-I agonist is in the form of an ApoA-I agonist-lipid complex, said complex comprising the ApoA-I agonist and a lipid.
39 . The pharmaceutical composition of claim 38 in which the ApoA-I agonist-lipid complex is in the form of a lyophilized powder.
40 . A method of treating a subject suffering from a disorder associated with dyslipidemia, said method comprising the step of administering to the subject an effective amount of the ApoA-I agonist of claim 1 .
41 . The method of claim 40 in which the ApoA-I agonist is in the form of a pharmaceutical composition, said composition comprising the ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent.
42 . The method of claim 40 in which the ApoA-I agonist is in the form of an ApoA-I agonist-lipid complex, said complex comprising the ApoA-I agonist and a lipid.
43 . The method of claim 40 in which the disorder associated with dyslipidemia is hypercholesterolemia.
44 . The method of claim 40 in which the disorder associated with dyslipidemia is cardiovascular disease.
45 . The method of claim 40 in which the disorder associated with dyslipidemia is atherosclerosis.
46 . The method of claim 40 in which the disorder associated with dyslipidemia is restenosis.
47 . The method of claim 40 , in which the disorder associated with dyslipidemia is HDL or ApoA-I deficiency.
48 . The method of claim 40 , in which the disorder associated with dyslipidemia is hypertriglyceridemia.
49 . The method of claim 40 , in which the disorder associated with dyslipidemia is metabolic syndrome.
50 . A method of treating a subject suffering from septic shock, said method comprising the step of administering to the subject an effective amount of the ApoA-I agonist of claim 1 .
51 . The method of claim 40 or 50 in which said subject is a human.
52 . The method of claim 40 or 50 in which about 0.5 mg/kg to about 100 mg/kg ApoA-I agonist is administered to said subject.Join the waitlist — get patent alerts
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