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

An ApoA-I agonist compound comprising:

• (i) an 18 to 22-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 -Z.sub.2 (I)
• X.sub.1 is Pro (P), Ala (A), Gly (G), Asn (N), Gln (Q) or D-Pro (p);
• X.sub.2 is an aliphatic amino acid;
• X.sub.3 is Leu (L);
• X.sub.4 is an acidic amino acid;
• X.sub.5 is Leu (L) or Phe (F);
• X.sub.6 is Leu (L) or Phe (F);
• X.sub.7 is a basic amino acid;
• X.sub.8 is an acidic amino acid;
• X.sub.9 is Leu (L) or Trp (W);
• X.sub.10 is Leu (L) or Trp (W);
• X.sub.11 is an acidic amino acid or Asn (N);
• X.sub.12 is an acidic amino acid;
• X.sub.13 is Leu (L), Trp (W) or Phe (F);
• X.sub.14 is a basic amino acid or Leu (L);
• X.sub.15 is Gln (Q) or Asn (N);
• X.sub.16 is a basic amino acid;
• X.sub.17 is Leu (L);
• X.sub.18 is a basic amino acid;
• 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 or 6-26 membered alkheteroaryl or a 1 to 4-residue peptide or peptide analogue in which one or more bonds between residues 1-7 are independently a substituted amide, an isostere of an amide or an amide mimetic;
• and
• each "-" between residues X.sub.1 through X.sub.18 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 or X.sub.18 is conservatively substituted with another residue.