Patent ID: 6734169
Filing Date: 2004-05-11
Classification: A61K,A61P,C07K

Abstract:
An ApoA-I agonist compound comprising:(i) an 18 to 22-residue peptide or peptide analogue which forms an amphipathic &agr;-helix in the presence of lipids and which comprises formula (I): Z1â€”X1â€”X2â€”X3â€”X4â€”X5â€”X6â€”X7â€”X8â€”X9â€”X10â€”X11â€”X12â€”X13â€”X14â€”X15â€”X16â€”X17â€”X18â€”Z2 â€ƒor a pharmaceutically acceptable salt thereof, wherein X1 is Pro (P), Ala (A), Gly (G), Asn (N), Gln (Q) or D-pro (p); X2 is an aliphatic residue; X3 is Leu (L); X4 is an acidic residue; X5 is Leu (L) or Phe (F); X6 is Leu (L) or Phe (F); X7 is a basic residue; X8 is an acidic residue; X9 is Leu (L) or Trp (W); X10 is Leu (L) or Trp (W); X11 is an acidic residue or Asn (N); X12 is an acidic residue; X13 is Leu (L), Trp (W) or Phe (F); X14 is a basic residue or Leu (L); X15 is Gln (Q) or Asn (N); X16 is a basic residue; X17 is Leu (L); X18 is a basic residue; wherein at least one L-enantiomeric residue of formula (I) other than Pro (P) at X1 is replaced with an identical D-enantiomeric residue; Z1 is H2Nâ€”, or RC(O)NRâ€”; Z2 is â€”C(O)NRR, â€”C(O)OR or â€”C(O)OH; 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 4-residue peptide or peptide analogue in which one or more bonds between residues 1 through 4 are independently a substituted amide, an isostere of an amide or an amide mimetic; each â€œâ€”â€  between residues X1 through X18 independently designates an amide linkage, a substituted amide linkage, an isostere of an amide or an amide mimetic; (ii) a 14 to 21-residue deleted peptide or peptide analogue according to formula (I) in which at least one and up to eight of residues X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17 and X18 are optionally deleted and wherein at least one remaining L-enantiomeric residue of formula I is replaced with an identical D-enantiomeric residue; or (iii) an 18 to 22-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 and X18 is conservatively substituted and wherein at least one L-enantiomeric residue of the resulting altered peptide or peptide analogue is replaced with an identical D-enantiomeric residue; or an N-terminally blocked form, a C-terminally blocked form or an N- and C-terminally blocked form of formula (I).