CRF2 receptor agonists and their use in therapy

1 . A compound which is a peptide, the peptide comprising the amino acid sequence of formula (I):

X1-X2-L-S-L-D-X7-P-X9-X10-X11-X12-X13-X14-L-X16-X17-Q-X19-X20-X21-X22-X23-X24-X25-X26-X27-A-X29-X30-X31-X32-X33-X34-L-X36-X37-X38   Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

X1 is isoleucine (I) or phenylalanine (F);

X2 is valine (V) or threonine (T);

X7 is valine (V) or D-valine (v);

X9 is isoleucine (I) or threonine (T);

X10 is lysine (K), glutamate (E), histidine (H), or glycine (G);

X11 is isoleucine (I) or leucine (L);

X12 is lysine (K), wherein the epsilon-amino group of the lysine side chain is covalently bound to an albumin-binding moiety;

X13 is glutamine (Q) or lysine (K);

X14 is isoleucine (I), lysine (K), or 2-aminoisobutyric acid (Aib);

X16 is leucine (L) or phenylalanine (F);

X17 is glutamate (E) or lysine (K);

X19 is alanine (A), glutamate (E), or glutamine (Q);

X20 is lysine (K) or arginine (R);

X21 is glutamine (Q) or lysine (K);

X22 is lysine (K), arginine (R), or glutamate (E);

X23 is lysine (K) or 2-aminoisobutyric acid (Aib);

X24 is glutamine (Q), 2-aminoisobutyric acid (Aib), leucine (L), or glutamate (E);

X25 is arginine (R), lysine (K), or 2-aminoisobutyric acid (Aib);

X26 is alanine (A), glutamate (E), 2-aminoisobutyric acid (Aib), or glutamine (Q);

X27 is glutamine (Q), 2-aminoisobutyric acid (Aib), or lysine (K);

X29 is glutamate (E) or lysine (K);

X30 is lysine (K) or threonine (T);

X31 is asparagine (N) or alanine (A);

X32 is lysine (K), alanine (A), valine (V), threonine (T), glutamate (E), or 2-aminoisobutyric acid (Aib);

X33 is arginine (R), lysine (K), or glutamine (Q);

X34 is isoleucine (I) or leucine (L);

X36 is alanine (A) or glutamate (E);

X37 is glutamine (Q) or arginine (R); and

X38 is isoleucine (I) or valine (V); and

wherein the albumin-binding moiety is a group of the formula (II):

—Z 1 —Y—Z 2 —C(O)R 1   (II)

wherein:

Y is AEEA, {AEEA} 2 , {AEEA} 3 , Gly, {Gly} 2 , {Gly} 3 , N-MeGly, {N-MeGly} 2 , {N-MeGly} 3 or absent, wherein Y is absent when Z 2 is gGlu, or {gGlu} 2 , and wherein AEEA denotes [2-(2-aminoethoxy)ethoxy]-acetyl;

Z 1 and Z 2 are each independently selected from gGlu, {gGlu} 2 , {gGlu} 3 , {gGlu} 4 or absent, wherein Z 1 is absent when Y is {AEEA} 2 and Z 2 is gGlu or {gGlu} 2 ; and

R 1 is —(CH 2 ) x COOH or —(CH 2 ) x CH 3 , wherein x is an integer from 12 to 22.

2 . The compound of claim 1 , wherein the albumin-binding moiety is selected from the following groups:

-(gGlu) n=1-4 -C(O)(CH 2 ) 14 CH 3 ;

-(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(gGlu) n=1-4 -C(O)(CH 2 ) 16 CH 3 ;

-(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH;

-(gGlu) n=1-4 -C(O)(CH 2 ) 18 CH 3 ;

-(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 CH 3 ;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 CH 3 ;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 CH 3 ;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 CH 3 ;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(gGlu) n=1-4 (AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 CH 3 ;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 CH 3 ; and

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH.

3 . The compound of claim 1 , wherein:

X1 is isoleucine (I);

X2 is valine (V);

X7 is valine (V) or D-valine (v);

X9 is isoleucine (I) or threonine (T);

X10 is lysine (K) or glycine (G);

X11 is leucine (L);

X13 is lysine (K) or glutamine (Q);

X14 is lysine (K) or isoleucine (I);

X16 is leucine (L);

X19 is alanine (A) or glutamate (E);

X21 is glutamine (Q);

X22 is glutamate (E), arginine (R) or lysine (K);

X23 is lysine (K) or 2-aminoisobutyric acid (Aib);

X24 is glutamate (E) or glutamine (Q) or 2-aminoisobutyric acid (Aib);

X25 is lysine (K) or arginine (R);

X26 is alanine (A), glutamate (E) or glutamine (Q);

X27 is 2-aminoisobutyric acid (Aib); lysine (K) or glutamine (Q);

X29 is glutamate (E);

X30 is lysine (K) or threonine (T);

X31 is asparagine (N);

X32 is lysine (K) or alanine (A);

X33 is arginine (R) or glutamine (Q);

X34 is isoleucine (I);

X36 is alanine (A) or glutamate (E);

X37 is arginine (R) or glutamine (Q); and

X38 is valine (V).

4 . The compound of claim 1 , wherein:

X7 is D-valine (v);

X10 is lysine (K) or glycine (G);

X19 is alanine (A) or glutamate (E);

X23 is 2-aminoisobutyric acid (Aib), or lysine (K);

X24 is 2-aminoisobutyric acid (Aib), or glutamine (Q);

X25 is arginine (R);

X26 is glutamine (Q), alanine (A) or glutamate (E);

X27 is glutamine (Q) or lysine (K);

X30 is threonine (T) or lysine (K);

X33 is arginine (R) or glutamine (Q);

X36 is alanine (A) or glutamate (E); and

X37 is arginine (R) or glutamine (Q).

5 . The compound of claim 1 , wherein:

X10 is lysine;

X19 is glutamate (E);

X24 is glutamine (Q);

X25 is arginine (R);

X26 is glutamate (E);

X27 is glutamine (Q);

X30 is lysine (K);

X33 is glutamine (Q);

X36 is alanine (A); and

X37 is glutamine (Q).

6 . The compound of claim 1 , wherein the compound is a peptide of the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof, optionally wherein the amino acid residue at X1 is acetylated, and optionally wherein the amino acid residue at X38 is amidated.

7 . The compound of claim 6 , wherein the amino acid residue at X38 is amidated as a C-terminal primary amide.

8 . The compound of claim 1 , wherein the albumin-binding moiety is selected from the following groups:

-(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH;

-(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH;

-(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 14 COOH;

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 16 COOH; and

-(gGlu) n=1-4 -(AEEA) n=1,2 -(gGlu) n=1-4 -C(O)(CH 2 ) 18 COOH.

9 . The compound of claim 1 , wherein the albumin-binding moiety is -{AEEA} 2 -gGlu-C(O)(CH 2 ) 14 COOH or -{AEEA} 2 gGlu-C(O)(CH 2 ) 16 COOH.

10 . The compound of claim 1 , wherein the compound is a peptide of any one of SEQ ID NOs: 1 to 227 or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 1 , wherein the compound is a peptide of any one of SEQ ID NOs: 3, 7, 35, 83, 130, 135, 136, 137, 138, 139, 140, 141, 142, 147, 149, 151, 152, 171, 172, 173, and 174, or a pharmaceutically acceptable salt thereof.

12 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier.