Growth Hormone Secretagogue Receptor 1A Ligands

• US 20080300180A1
• Filed: 11/29/2005
• Published: 12/04/2008
• Est. Priority Date: 11/30/2004
• Status: Abandoned Application

• Current Assignee: Gastrotech Pharma A/S
• Original Assignee: Gastrotech Pharma A/S
• Inventors: Jensen, Peter Holme, Schambye, Hans T., Lange, Birgitte Holst
• Application Number:
  US11/720,477
• Publication Number:
  US 20080300180A1
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: C07K 14/60 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic

Abstract

The present invention relates to new growth hormone secretagogue receptor 1A (GHS-R 1A) ligands, and pharmaceutical compositions comprising any of the new GHS-R1 A ligands. The ligands are suitable for a wide range of applications, and thus the present invention also relates to use of the GHS-R1 A ligands according to the present invention in the manufacture of a medicament for the treatment of an individual in need thereof. In another aspect, the present invention relates to a method of treatment of an individual in need thereof, comprising administering to said individual one or more of the GHS-R1A ligands disclosed herein, such as e.g. for treatment of cancer cachexia.

Claims

1. A GHS-R1A ligand compound or a pharmaceutically acceptable salt thereof

wherein the GHS-R1A ligand compound has a structure defined by formula I′

Z²-(X³)_n-(X²)_m(X¹)_mZ³-Z¹

wherein Z¹ is an optionally present protecting group,

each X¹ is an amino acid independently selected from naturally occurring and synthetic amino acids,

X² is an anchor group, selected from naturally occurring and synthetic amino acids, said amino acid being modified,

each X³ is independently selected from an amino acid, wherein said amino acid is selected from naturally occurring and synthetic amino acids, with the proviso that at least one (X³) is a D-amino acid,

Z² is an optionally present protecting group,

Z³ is an optionally present linker or C-terminal group,

m is 0 or an integer in the range of 1-3

n is 0 or an integer in the range of 1-35,

and wherein both n and m cannot be 0.

2. The compound according to claim 1, wherein Z³ is selected from the groups

consisting of:

a) β

Ala or

b) X¹-β

Ala or

c) GABA or

d) X¹-GABA or

e) -X¹-Aminopentanoyl or

f) hydroxy acetic acid (HAA) or

g) X¹-HAA or

h) a compound with formula B, shown below;

3. The compound according claim 1, wherein X² is selected from the group consisting of:

modified Ser, modified Cys and modified Lys.

4. The compound according to claim 1, wherein the GHS-R1A ligand compound is selected from the group consisting of:

a compound of formula II′

Z²-(X³)_n-(X²)-(X¹)_m-1-Gly-Z¹,

a compound of formula III′

Z²-(X³)_n-(X²)-D-Ser-Gly-Z¹,

a compound of formula IV′

Z²-(X³)_n-(X²)-D-Ser-Gly-Z¹,

a compound of formula V′

Z²-(X³)_n-D-Ser-Z³-Z¹.

5. The compound according to claim 4, wherein the GHS-R1A ligand compound has formula III′

.

6. The compound according to claim 1, comprising a structure having the formula VI′

;

7. The compound according to claim 1, wherein (X³)_n comprises a sequence selected from one or more of the sequences shown below:

8. The compound according to claim 1, wherein n is an integer in the range of 1-25.

9. The compound according to claim 1, wherein (X³)_n is selected from one or more of the sequences shown below:

10. The compound according to claim 1, wherein the anchor group is selected from a C1-C35 acyl group.

11. The compound according to claim 1, wherein the anchor group is selected from the group consisting of:

C7 acyl group, C8 acyl group, C9 acyl group, C10 acyl group, C11 acyl group and C12 acyl group.

12. The compound according to claim 1, wherein the anchor group is selected from the group consisting of:

C8 acyl group and C10 acyl group.

13. The compound according to claim 1, wherein the anchor group is selected from the group consisting of:

C7 acyl group, C9 acyl group, and C11 acyl group.

14. The compound according to claim 1, wherein the anchor group is selected from the group consisting of:

(a) a glycerophospholipid

(b) a sterol moiety

(c) a sphingolipid moiety

(d) a ceramide or an analogue thereof

(e) an isoprenoid pyrophosphate

(f) a glycosyl-phosphatidylinositol (GPI) anchor and

(g) a phosphatidyl serine, or analogue thereof;

15. The compound according to claim 1, wherein the anchor group selected from any of the following:

a glycerophosphate with the following structure;

16. The compound according to claim 1, wherein said compound has a sequence according to SEQ ID NO:

4.

17. The compound according to claim 1, wherein said compound has a sequence according to SEQ ID NO:

10.

114. The compound according to claim 13, wherein X² is selected from the group consisting of:

modified Ser, modified Cys and modified Lys.

123. A pharmaceutical composition comprising the GHS-R1A ligand compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, vehicles and/or excipients.

124. The pharmaceutical composition according to claim 123, wherein said composition further comprises transport molecules, such as liposomes, micelles, iscoms, and/or microspheres.

125. A medical packaging comprising one or more dosage units of the pharmaceutical composition as defined in claim 123.

132. A method of treatment of a growth hormone secretagogue receptor 1A (GHS-R1A) associated disorder comprising administering a therapeutically effective amount of a GHS-R1A ligand compound according to claim 1 to an individual in need thereof.

133. The method of claim 132 wherein the compound is administered subcutaneously.

134. A method of treatment of a pathological condition treatable with a GHS-R1A ligand comprising administering a therapeutically effective amount of a GHS-R1A ligand compound according to claim 1 to an individual in need thereof.

135. The method of claim 132 comprising treatment of cachexia and/or malnutrition.

136. A method of simulating appetite, food intake and/or weight gain, and/or increasing body fat mass and/or lean body mass, comprising administering a therapeutically effective amount of a GHS-R1A ligand compound according to claim 1 to an individual in need thereof.

137. A method of maintaining metabolic homeostasis comprising administering a therapeutically effective amount of a GHS-R1A ligand compound according to claim 1 to an individual in need thereof.

18-111. -111. (canceled)

112. A GHS-R1A ligand compound or a pharmaceutically acceptable salt thereof,

wherein the GHS-R1A ligand compound has a structure defined by formula I′

″

Z¹-R¹-(X²)-(X³)_n-Z², wherein

Z¹ is an optionally present protecting group;

R¹ is selected from the group consisting of;

a) β

Ala-,

b) β

Ala-X1-,

c) GABA-,

d) GABA-X1-

e) Aminopentanoyl-X1,

f) hydroxy acetic acid (HAA)-,

g) HAA-X1- and

h) a compound with formula B, shown below;

113. The GHS-R1A ligand compound according to claim 112, wherein R¹ is selected from the group consisting of:

a) β

Ala-

b) β

Ala-X¹-

c) GABA-

d) GABA-X¹-

e) hydroxy acetic acid (HAA)-

f) HAA-X¹- and

g) a compound with formula B, shown below;

115. The compound according to claim 113, wherein X² is selected from the group consisting of:

a) decenoic acid (L or D form),

b) 5-hexenoic acid (L or D form),

c) 6-heptenoic acid (L or D form),

d) 7-octenoic acid (L or D form),

e) 8-nonenoic acid (L or D form),

f) Ala-3-cp (L or D form),

g) Ala-3-cb (L or D form),

h) Phe-4-Me (L or D form),

i) Phe-4-Et (L or D form),

j) Phe-4-iPr (L or D form),

k) Phe-4-Ph (L or D form),

l) Beta-MeTrp (L or D form),

m) Ala[3-(3-Quinolinyl)] (L or D form),

n) Ala[3-(2-benzimidazoyl)] (L or D form),

o) BenzoTrp (L or D form),

p) 7-AzaTrp (L or D form) and

q) Trp(5-NH2) (L or D form);

116. The compound according to claim 112, wherein the GHS-R1A ligand compound is selected from the group consisting of:

Z¹-β

Ala-(X²)-(X³)_n-Z², 

 

formula II′

″

Z¹-β

Ala-Ser-(X²)-(X³)_n-Z², 

 

formula III′

″

Z¹-GABA-(X²)-(X³)_n-Z², 

 

formula IV′

″

Z¹-GABA-Ser-(X²)-(X³)_n-Z², 

 

formula V′

″

Z¹-Aminopentanoyl-Ser-(X²)-(X³)_n-Z², 

 

formula VII′

″

Z¹-HAA-Ser-(X²)-(X³)_n-Z², 

 

formula VIII′

″

Z¹-HAA-(X²)-(X³)_n-Z² 

 

formula IX′

″

wherein Z¹ and Z² are optional protecting groups.

117. The compound according to any of claims 112-116, wherein n is an integer in the range of 1-25.

118. The compound according claim 112, wherein (X³)_n is as defined in claims 7-8.

119. The compound according to claim 112, wherein the anchor group is selected from a C1-C35 acyl group.

120. The compound according to claim 112, wherein said compound has SEQ ID NO:

8.

121. The compound according to claim 112, wherein said compound has SEQ ID NO:

9.

122. The compound according to claim 112, wherein said compound consists of any of the sequences with SEQ ID NO:

19-29.

126-131. -131. (canceled)