Peptide derivatives and related uses as orexin agonists

A peptide having a sequence comprising:

• (SEQ ID NO:
• 1)
• Z1X1X2X3X4X5X6X7X8X9X10X11X12-NH2,
• or
• (SEQ ID NO:
• 2)
• Z1X1X2X3X4X5X6X7X8X9X10X11X12-NH2,
• or an isomer, pharmaceutically acceptable salt, or prodrug of any one thereof, wherein, when the peptide comprises SEQ ID NO:1,
• Z1 is a capping group, Arg, or hArg(Et)2;
• X1 is absent or an amino acid comprising a polar uncharged side chain, or a derivative thereof;
• X2 is absent or an amino acid comprising an electrically charged side chain, or a derivative thereof;
• X3 is Gly or a Gly derivative;
• X4 is an amino acid comprising a polar uncharged side chain, or a derivative thereof,
• X5 is an amino acid comprising a polar charged side chain, or a derivative thereof,
• X6 is an amino acid comprising a hydrophobic side chain, or a derivative thereof,
• X7 is Gly, a Gly derivative, or Nag(1);
• X8 is Gly or a Gly derivative;
• X9 is an amino acid comprising a hydrophobic side chain, or a derivative thereof,
• X10 is an amino acid comprising a hydrophobic side chain, or a derivative thereof;
• X11 is an amino acid comprising a polar uncharged side chain, or a derivative thereof;
• and
• X12 is 2-AOC, 2-AHP, NLE, NVA, Phe or Phe(3-Br), wherein the phenyl of X12 is optionally substituted with halo, —OH, —O(C1-C6alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• or
• when the peptide comprises SEQ ID NO:
• 2,
• Z1 is a capping group, Arg, or hArg(Et)2;
• X1 is absent, Gln, Asn, N-Me-Asn, Thr, or Ser;
• X2 is absent, Arg, hArg(Et)2, Hyp(4-OH), His, Lys, Asp, or Glu;
• X3 is N-Phenethyl-Gly, N-(naphthalen-2-yl-ethyl)-Gly, N-(naphthalen-1-yl-ethyl)-Gly, N-(3-EtNH2-Phenethyl)-Gly, N-(4-OMe-Phenethyl)-Gly, Phg, Phg(4-OH), or Gly, wherein the phenyl of X3 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X4 is Asn, N-Me-Asn, Ser, Thr, or Gln;
• X5 is Hyp(4-OH), His, Arg, Lys, Asp, Gln, or Glu;
• X6 is Ala, Val, Ile, Leu, Met, Phe, Tyr, or Trp, wherein the phenyl of X6 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X7 is Phg, Phg(4-OH), Phg(3-OH), Phg(4-Ome), N-Phenethyl-Gly, N(naphtha-2-yl-ethyl)-Gly, N-(4-Ome-Phenethyl)-Gly, Gly, or Nag(1), wherein the phenyl of X7 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X8 is Phg, Phg(4-OH), N-Phenethyl-Gly, N(naphtha-2-yl-ethyl)-Gly, N-(4-Ome-Phenethyl)-Gly, or Gly, wherein the phenyl of X8 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X9 is Ile, Ala, Val, Leu, Met, Phe, Tyr, or Trp, wherein the phenyl of X9 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X10 is N-Me-Leu, Leu, Ala, Val, Ile, Met, Phe, Tyr, or Trp, wherein the phenyl of X10 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• X11 is Thr, Ser, Asn, or Gln;
• and
• X12 is 2-AOC, 2-AHP, NLE, NVA, Phe, or Phe(3-Br), wherein the phenyl of X12 is optionally substituted with halo, —OH, —O(C1-C6 alkyl), —CN, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.