Patent ID: 6573239
Filing Date: 2003-06-03
Classification: A61K,A61P,C07K

Abstract:
An ApoA-I agonist compound comprising:(i) 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): Z1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-Z1 or a pharmaceutically acceptable salt thereof, 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 (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; Z1 is H2Nâ€” or RC(O)NRâ€²â€”; Z2 is â€”C(O)NRR, â€”C(O)OR or â€”C(O)OH or a salt thereof; 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 or 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; and 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; and each â€œ-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 an N-terminally blocked form, a C-terminally blocked form, or an N- and C-terminally blocked form of formula (I).