Patent ID: 6753313
Filing Date: 2004-06-22
Classification: A61K,A61P,C07K

Abstract:
A multimeric ApoA-I agonist compound which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has formula (II):Z1â€”HHLLmâ€”HHnLLmâ€”HHâ€”Z2â€ƒâ€ƒ(II) or a pharmaceutically acceptable salt thereof, wherein:Z1 is H2Nâ€” or RC(O)NRâ€²â€”; Z2 is â€”C(O)NRR or â€”C(O)OR; each R is independently â€”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 1-7 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 Râ€² is independently â€”H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl; each m is independently an integer from 0 to 1; n is an integer from 0 to 10; each â€œLLâ€  is independently a bifunctional linker; each â€œâ€”â€  independently designates a covalent linkage; and each HH is independently: (i) a 22 to 29-residue peptide or peptide analogue which forms an amphipathic &agr;-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-X23â€ƒâ€ƒ(I) â€ƒwherein: 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 (G); 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 Gln (Q), Asn (N) or a basic residue; X19 is Gln (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 â€œâ€”â€  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 forms an amphipathic &agr;-helix in the presence of lipids and 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) a 22 to 29-residue altered peptide or peptide analogue according to 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 or X23 is conservatively substituted with another residue; or an N-terminally blocked form, a C-terminally blocked form or an N- and C-terminally blocked form of formula (II).