Patent ID: 6329341
Filing Date: 2001-12-11
Classification: A61K,A61P,C07K

Abstract:
A method of treating a subject suffering from septic shock, said method comprising the step of administering to the subject an effective amount of 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 has the 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.2or 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) or Asn (N) or a basic residue;X.sub.19 is Gln (Q) or 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, an isostere of an amide or an amide mimetic; andeach ""-"" between residues X.sub.1 and X.sub.23 independently designates an amide linkage, a substituted amide linkage, an isotere of an amide or an amide mimetic; or(ii) a 15 to 28 residue deleted form of formula (I) in which at least one and up to eight 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 and X.sub.22 are deleted; or(iii) 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.