TREATMENT OF CARDIAC CONDITIONS

• US 20130157953A1
• Filed: 01/20/2011
• Published: 06/20/2013
• Est. Priority Date: 01/20/2010
• Status: Abandoned Application

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Meier, Eddi, Larsen, Bjarne Due, Petersen, Jrgen Sberg, Kjoelbye, Anne Louise, Skovgaard, Marie, Pedersen, Henrik Duelund, Axelsen, Lene, Riber, Ditte, Hansen, Rie Schultz, Fosgerau, Keld
• Application Number:
  US13/574,197
• Publication Number:
  US 20130157953A1
• Time in Patent Office: Days
• US Class Current: 514/11.7
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The invention relates to the treatment of cardiac dysfunction. In particular, certain compounds, believed to be glucagon-GLP-1 dual agonist compounds, exert a positive inotropic effect while preserving the energy balance of the heart, and so may be superior to known inotropic agents such as dobutamine, norepinephrine and glucagon.

Claims

1. A method of treating heart disease or heart dysfunction in a subject, comprising administering a glucagon-GLP-1 dual agonist to the subject as a positive inotropic agent.

2. The method according to claim 1, wherein said heart disease or heart dysfunction is selected from the group consisting of:

congestive heart failure, systolic dysfunction, diastolic dysfunction, myocardial infarction, ischemic heart disease, diabetic cardiomyopathy and combinations thereof.

5. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist is administered in combination with an agent for treatment of a condition selected from heart failure, diabetes, obesity, myocardial infarction, hypolipidemia and hypertension.

6. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist is a compound having the formula:

R¹—

X—

Z¹—

Z²—

R²

wherein;

R¹ is hydrogen, C_1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;

X has the Formula I;

30. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R¹—

X—

Z²—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the Formula III;

41. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R¹—

X—

Z²—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the Formula V;

46. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R¹—

X—

Z²—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the Formula VI;

54. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R¹—

X—

Z¹—

Z²—

R²

wherein;

R¹ is hydrogen, C_1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;

wherein X has the Formula VII;

55. The method according to claim 54, wherein X differs from Formula VII by 1 to 3 amino acid modifications at positions selected from 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, 24, 27, 28 and 29.

119. The method according to claim 6, wherein Z² is absent.

120. The method according to claim 6, wherein Z¹ is absent.

123. The method according to claim 6, wherein one or more of the amino acid side chains of the glucagon-GLP-1 agonist is conjugated to a lipophilic substituent.

134. The method according to claim 123, wherein each lipophilic substituent comprises a lipophilic moiety conjugated to the amino acid side chain by a spacer.

135. A method according to claim 134 wherein the combination of lipophilic moiety and spacer is selected from dodecanoyl-γ

-Glu, hexadecanoyl-γ

-Glu, hexadecanoyl-Glu, hexadecanoyl-[3-aminopropanoyl], hexadecanoyl-[8-aminooctanoyl], hexadecanoyl-ε

-Lys, 2-butyloctanoyl-γ

-Glu, octadecanoyl-γ

-Glu and hexadecanoyl-[4-aminobutanoyl].

3-4. -4. (canceled)

7-29. -29. (canceled)

31-40. -40. (canceled)

42-45. -45. (canceled)

47-53. -53. (canceled)

56-118. -118. (canceled)

121-122. -122. (canceled)

124-133. -133. (canceled)

136-154. -154. (canceled)