Branched multimeric Apo A-I agonist compounds

A multimeric ApoA-I agonist compound which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has the formula (IV) or (V):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is —OR or —NRR;
• each R is independently —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl, 6-26 membered alkheteroaryl;
• each X is independently Z1-HH-Z2 or Z1-HH[Parenopenst]LLm-HH[Parenclosest]nLLm-HH-Z2;
• Z1 is H2N— or R′C(O)NR—;
• Z2 is —C(O)NR′R′ or —C(O)OR′;
• each R′ is independently —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) 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, an isostere of an amide or an amide mimetic;
• each R is independently —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl, 6-26 membered alkheteroaryl;
• 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;
• and
• each HH is independently:
• (i) a 22 to 29-residue peptide or peptide analogue which forms an amphipathic α-helix in the presence of lipids and which comprises formula (I):
• X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23 (I)
• wherein:
• X1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
• X2 is an aliphatic residue;
• X3 is Leu (L) or Phe (F);
• X4 is an acidic residue;
• X5 is Leu (L) or Phe (F);
• X6 is Leu (L) or Phe (F);
• X7 is a hydrophilic residue;
• X8 is an acidic or a basic residue;
• X9 is Leu (L) or Gly (G);
• X10 is Leu (L), Trp (W) or Gly (Q);
• X11 is a hydrophilic residue;
• X12 is a hydrophilic residue;
• X13 is Gly (G) or an aliphatic residue;
• X14 is Leu (L), Trp (W), Gly (G) or Nal;
• X15 is a hydrophilic residue;
• X16 is a hydrophobic residue;
• X17 is a hydrophobic residue;
• X18 is Gin (Q), Asn (N) or a basic residue;
• X19 is Gin (Q), Asn (N) or a basic residue;
• X20 is a basic residue;
• X21 is an aliphatic residue;
• X22 is a basic residue;
• X23 is absent or a basic residue;
• and
• each “-” between residues X1 through X23 independently designates an amide linkage, a substituted amide linkage, an isostere of an amide or an amide mimetic;
• or
• (ii) a 15 to 26-residue peptide or peptide analogue according to formula (I) which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I wherein one or two helical turns are deleted from formula (I), wherein a helical turn consists of 3 to 4 consecutive residues selected from residues X1 to X23 of formula (I);
• or
• (iii) an altered form of formula (I) in which at least one of residues X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23 is conservatively substituted with another residue;
• or
• an N- terminally blocked form or a C-terminally blocked form of formula (IV) or (V).