Oxyntomodulin analogs

Patent metadata

Field	Value
Publication number	US-9593155-B2
Application number	US-201514686760-A
Country	US
Kind code	B2
Filing date	Apr 14, 2015
Priority date	Feb 19, 2009
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

Peptide analogs of oxyntomodulin (OXM, glucagon-37), which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to act as a dual GLP-1/glucagon receptor (GCGR) agonist are described. The peptide analogs are useful for treatment of metabolic disorders such as diabetes and obesity.

First claim

What is claimed:

1. A peptide analog comprising:
Z1-P-M-Z2
wherein P is a peptide having the amino acid sequence

(SEQ ID NO: 110)

HX1QGTFTSDX2SX3YLDX4X5X6AX7DFVQWLX8NTKX9X10

wherein X1 is a D-serine, α-aminoisobutyric acid (aib), 1-Amino-1-cyclobutane carboxylic acid (Acb) residue, 1-Amino-1-cyclohexane carboxylic acid (Acx); alpha-aminobutyric acid (Abu); D-alpha-aminobutyric acid (D-Abu); Aminovaleric acid (Nva); beta-cyclopropyl-alanine (Cpa); propargylglycine (Prg); Allylglycine (Alg); 2-Amino-2-cyclohexyl-propanoic acid (2-Cha); D-tertbutylglycine (D-tbg); Vinylglycine (Vg); 1-Amino-1-cyclopropane carboxylic acid (Acp); or 1-Amino-1-cyclopentane carboxylic acid (Acpe) residue;
X2 is a tyrosine (Y) or lysine (K) residue;
X3 is serine (S) or lysine (K) residue;
X4 is serine (S), α-aminoisobutyric acid (aib), or glutamic acid (E) residue;
X5 is an arginine (R) or glutamic acid (E) residue;
X6 is an arginine (R) or alanine (A) residue;
X7 is a glutamine (Q) or lysine (K) residue;
X8 is a methionine (M), norleucine (Nle), methionine sulfoxide (m), or O-methyl-L-homoserine (o) residue;
X9 is a gamma glutamic acid (γGlu) residue;
X10 is a gamma glutamic acid (γGlu) residue or absent;
Z1 is an optionally present protecting group that, if present, is joined to the N-terminal amino group,
M is (i) a cysteine residue covalently linked to a cholesterol moiety by a hydrophilic linker, (ii) a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues, or (iii) a lipid moiety, wherein M is covalently linked to a C-terminal or internal amino acid of P by a spacer comprising one or more gamma-glutamic acid residues; and
Z2 is an optionally present protecting group that, if present, is joined to the C-terminal carboxy group; and pharmaceutically acceptable salts thereof,
wherein the peptide analog or salt thereof has a pI of less than 6.0 and is a dual GLP-1 receptor agonist and glucagon receptor agonist.

2. The peptide analog of claim 1 , wherein M is a cysteine residue covalently linked to a cholesterol moiety with a hydrophilic linker and the cysteine residue is linked to the C-terminus of P.

3. The peptide analog of claim 1 , wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is linked to the C-terminus of P.

4. The peptide analog of claim 1 , wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is at position X2 or X7 of P.

5. The peptide analog of claim 1 , wherein the hydrophilic linker is an ethoxy polymer that includes one to twenty-four ethoxy units.

6. The peptide analog of claim 1 , wherein the hydrophilic linker is an ethoxy polymer that includes four ethoxy units.

7. The peptide analog of claim 1 , wherein the lipid moiety is a palmitoyl moiety.

8. The peptide analog of claim 1 , wherein the peptide analog is OXM319 (SEQ ID NO:62); OXM327 (SEQ ID NO:66); OXM329 (SEQ ID NO:67); OXM383 (SEQ ID NO:78); or OXM388 (SEQ ID NO:79).

9. The peptide analog of claim 1 wherein M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is linked to the C-terminus of P or M is a lysine residue covalently linked to a lipid moiety by a spacer comprising one or more gamma glutamic acid residues and the lysine residue is at position X2 or X7 of P.

10. The peptide analog of claim 9 , wherein the lipid moiety is a palmitoyl, myristoyl, or stearoyl moiety.

Assignees

• Merck Sharp & Dohme
• St Di Ricerche Di Biologia P Angeletti S R L
• Univ Indiana Res & Tech Corp
• Msd Italia Srl

Inventors

• Carrington Paul E
• Eiermann George J
• Marsh Donald J
• Metzger Joseph M
• Pocai Alessandro
• Sinha Roy Ranabir
• Bianchi Elisabetta
• Ingallinella Paolo
• Pessi Antonello
• Santoprete Alessia
• Capito Elena
• Dimarchi Richard
• Ward Brian

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K14/575

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title