Long-acting co-agonists of the glucagon and glp-1 receptors
AssigneeMerck Sharp & Dohme Corp.
InventorsAnandan Palani, Ravi Nargund, Paul E. Carrington, Tomi Sawyer, Qiaolin Deng, Antonello Pessi, Elisabetta Bianchi, Federica Orvieto
Life of this patent
Estimating the term…
Abstract
Long-acting co-agonists of the glucagon and GLP-1 receptors are described.
Claims49
A peptide comprising the formula
- (SEQ ID NO:
- 50)
- HX2QGTFTSX9X10SX12YX14DX16RAAX20X21X22VX24WLX27X28TX30-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or D-Ser or alpha-Methyl-L-Serine (alpha-MS);
- X9 is Asp or alpha-Methyl-L-Aspartic acid (alpha-MD);
- X10 is Lys conjugated to a fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a fatty diacid or Tyr;
- X12 is Lys conjugated to a fatty diacid, pAF conjugated to a fatty diacid, Lys, or βc, or (1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid;
- X14 is Leu or alpha-L-Leucine (alpha-ML);
- X16 is aib, Ala, or Glu;
- X20 is Lys is conjugated to a fatty diacid, pAF conjugated to a fatty diacid, or Gln;
- X21 is Lys conjugated to a fatty diacid or pAF conjugated to a fatty diacid, Asp, or alpha-MD;
- X22 is Phe or alpha-Methyl-L-phenylalanine (alpha-MF);
- X24 is Gln or βc or (1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid, or Lys conjugated to a fatty diacid or pAF conjugated to a fatty diacid;
- X27 is L-Met sulphone or Leucine;
- X28 is Asp, or alpha-MD, or alpha-Methyl-L-Tryptophan (alpha-MW), Lys, or Ala, or Lys conjugated to a fatty diacid, or pAF conjugated to a fatty diacid;
- and
- X30 is Lys linked at the C-terminus to gamma-Glu when X27 is Leu and X28 is Ala;
- with the proviso that for each co-agonist peptide, only one of X10, X12, X20, X21, X24, or X28 is conjugated to a fatty diacid.
A peptide comprising the formula
- (SEQ ID NO:
- 51)
- HX2QGTFTSDX10SKYLDX16RAAQFVQWLX27X28TX30-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or D-Ser;
- X10 is Lys conjugated to a C16 or C18 or C20 fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16 or C18 or C20 fatty diacid;
- X16 is aib, Ala, or Glu;
- X27 is L-Met sulphone or Leucine;
- X28 is Asp, Lys, or Ala;
- and
- X30 is Lys conjugated to gamma-Glu when X27 is Leu and X28 is Ala or absent.
A peptide comprising the formula
- (SEQ ID NO:
- 52)
- HX2QGTFTSDYSX12YLDX16RAAQDFVQWLX27DT-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or D-Ser;
- X12 is Lys conjugated to a C16 or C18 or C20 fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16 or C18 fatty diacid;
- X16 is aib, Ala, or Glu;
- and
- X27 is L-Met sulphone or Leucine.
A peptide comprising the formula
- (SEQ ID NO:
- 53)
- HX2QGTFTSX9YSX12YX14DX16RAAX20X21X22VX24WX26X27X28T-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or D-Ser;
- X9 is Asp or alpha-MD;
- X12 is Lys or (1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid (βc);
- X14 is Leu or alpha-Methyl-L-Aspartic acid (alpha-MD);
- X16 is aib, Ala, or Glu;
- X29 is Lys conjugated to a C16, C17, C18, C19, or C20 fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16, C17, C18, C19, or C20 fatty diacid;
- X21 is Asp or alpha-MD;
- X22 is Phe or alpha-Methyl-L-phenylalanine (alpha-MF);
- X24 Gln or βc;
- X27 is L-Met sulphone or Leucine;
- and
- X28 is Asp, Lys, or alpha-MD.
A peptide comprising the formula
- (SEQ ID NO:
- 54)
- HX2QGTFTSDYSKYLDX16RAAQX21FVQWLX27X28TX30-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or D-Ser;
- X16 is aib, Ala, or Glu;
- X21 is Lys conjugated to a C16, C17, C18, C19, or C20 fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16, C17, C18, C19, or C20 fatty diacid;
- X27 is L-Met sulphone or Leucine;
- X28 is Asp, Lys, or Ala;
- and
- X30 is Lys conjugated to gamma-Glu when X27 is Leu and X28 is Ala.
A peptide comprising the formula
- (SEQ ID NO:
- 80)
- HX2QGTFTSDYSKYLDX16RAAX20X21FVX24X25LX27X28T-NH2
- wherein
- X2 is aminoisobutyric acid (aib) or alpha-Methyl-L-Serine (alpha-MS);
- X16 is aib or Ala;
- X20 is Gln or Lys conjugated to a C16, C17, C18, C19, or C20 fatty diacid;
- X21 is Asp or Lys conjugated to a C16, C17, C18, C19, or C20 fatty diacid or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16, C17, C18, C19, or C20 fatty diacid;
- X24 is Gln or Lys conjugated to a C16, C17, C18, C19, or C20 fatty diacid;
- X25 is Trp or alpha-Methyl-L-Tryptophan (alpha-MW);
- X27 is L-Met sulphone or Leucine;
- and
- X28 is Asp or alpha-Methyl-L-Aspartic acid (alpha-MD) or p-aminomethyl-L-phenylalanine (pAF) conjugated to a C16, C17, C18, C19, or C20 fatty diacid, with the proviso that one of X20, X21, or X28 is conjugated to the C16, C17, C18, C19, or C20 fatty diacid.
A peptide selected from TP340, TP342, TP344, TP369, TP370, TP371, TP372, TP378, TP379, TP380, TP382, TP383, TP384, TP403, TP404, TP406, TP407, TP408, TP409, TP410, TP413, TP416, TP417, TP418, TP419, TP422, TP423, TP424, TP440, TP441, TP442, TP443, TP458, TP461, TP467, TP470, TP472, TP473, TP474, TP475, TP476, TP477, TP491, TP492, TP493, TP494, TP495, TP496, TP560, TP575, TP564, TP598, TP608, TP655, TP654, TP628, TP609, TP597, TP604, TP630, and TP640.
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Dependencies are inferred from the claim text.