Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders

An ApoA-I agonist compound comprising:

• (i) a 22 to 29-residue peptide or peptide analogue which forms an amphipathic .alpha.-helix in the presence of lipids and which comprises formula (I):
• Z.sub.1 -X.sub.1 -X.sub.2 -X.sub.3 -X.sub.4 -X.sub.5 -X.sub.6 -X.sub.7 -X.sub.8 -X.sub.9 -X.sub.10 -X.sub.11 -X.sub.12 -X.sub.13 -X.sub.14 -X.sub.15 -X.sub.16 -X.sub.17 -X.sub.18 -X.sub.19 -X.sub.20 -X.sub.21 -X.sub.22 -X.sub.23 -Z.sub.2
• or a pharmaceutically acceptable salt thereof, wherein:
• X.sub.1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
• X.sub.2 is an aliphatic residue;
• X.sub.3 is Leu (L) or Phe (F);
• X.sub.4 is an acidic residue;
• X.sub.5 is Leu (L) or Phe (F);
• X.sub.6 is Leu (L) or Phe (F);
• X.sub.7 is a hydrophilic residue;
• X.sub.8 is an acidic or a basic residue;
• X.sub.9 is Leu (L) or Gly (G);
• X.sub.10 is Leu (L), Trp (W) or Gly (G);
• X.sub.11 is a hydrophilic residue;
• X.sub.12 is a hydrophilic residue;
• X.sub.13 is Gly (G) or an aliphatic residue;
• X.sub.14 is Leu (L), Trp (W), Gly (G) or Nal;
• X.sub.15 is a hydrophilic residue;
• X.sub.16 is a hydrophobic residue;
• X.sub.17 is a hydrophobic residue;
• X.sub.18 is Gln (Q), Asn (N) or a basic residue;
• X.sub.19 is Gln (Q), Asn (N) or a basic residue;
• X.sub.20 is a basic residue;
• X.sub.21 is an aliphatic residue;
• X.sub.22 is a basic residue;
• X.sub.23 is absent or a basic residue;
• Z.sub.1 is H.sub.2 N-- or RC(O)NH--;
• Z.sub.2 is --C(O)NRR, --C(O)OR or --C(O)OH or a salt thereof;
• each R is independently --H, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) alkynyl, (C.sub.5 -C.sub.20) aryl, (C.sub.6 -C.sub.26) alkaryl, 5-20 membered heteroaryl, 6-26 membered alkheteroaryl or a 1 to 7-residue peptide or peptide analogue in which one or more bonds between residues 1-7 are independently a substituted amide, and isostere of an amide or an amide mimetic;
• and
• each "--" between residues X.sub.1 through X.sub.23 independently designates an amide linkage, a substituted amide linkage, an isostere of an amide or an amide mimetic;
• or
• (ii) an altered form of formula (I) in which at least one of residues X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11, X.sub.12, X.sub.13, X.sub.14, X.sub.15, X.sub.16, X.sub.17, X.sub.18, X.sub.19, X.sub.20, X.sub.21, X.sub.22 or X.sub.23 is conservatively substituted with another residue.