Adiponectin receptor agonists and methods of use

1. A compound of Formula I:

X-M1-SEQ ID NO:1-M2-Z  (I)

wherein SEQ ID NO:1 is Xaa1-Ile-Pro-Xaa2-Leu-Tyr-Xaa3-Phe-Ala-Xaa4-Xaa5, wherein:

(a) Xaa1 is Asn or a non-natural amino acid;

(b) Xaa2 is Gly or a non-natural amino acid;

(c) Xaa3 is Tyr or a non-natural amino acid;

(d) Xaa4 is Tyr or a non-natural amino acid;

(e) Xaa5 is no amino acid, β-Ala or β-AlaNH 2 ;

provided, at least one of Xaa1, Xaa2, Xaa3, or Xaa4 is a non-natural amino acid;

X is an optionally present

1-10 amino acid peptide,

linear or branched polyethylene glycol having a molecular weight of from 1 kDa to 200 kDa,

lipophilic compound or

peptide transduction domain;

Z is an optionally present

1-10 amino acid peptide,

linear or branched polyethylene glycol having a molecular weight of from 1 kDa to 200 kDa,

lipophilic compound or

peptide transduction domain;

M1 is an optionally present single bond or a linking group; and

M2 is an optionally present single bond or a linking group;

wherein, when the compound of formula I comprises a C-terminal amino acid, said C-terminal amino acid is optionally amidated;

or a salt thereof.

2. The compound of claim 1 , or a salt thereof, wherein

(a) Xaa1 is D-Asn; and

(b) Xaa4 is D-Ser.

3. The compound of claim 1 , or a salt thereof, wherein Xaa2 is Nva.

4. The compound of claim 1 , or a salt thereof, wherein Xaa3 is D-Ser.

5. The compound of claim 1 , or a salt thereof, wherein

(a) Xaa2 is Nva; and

(b) Xaa3 is D-Ser.

6. The compound of claim 1 , or a salt thereof, wherein

(a) Xaa1 is D-Asn;

(b) Xaa2 is Nva;

(c) Xaa3 is D-Ser; and

(d) Xaa4 is D-Ser.

7. The compound of any one of claims 1 - 6 , or a salt thereof, wherein Xaa5 is β-Ala or β-AlaNH 2 .

8. The compound of any one of claims 1 - 6 , according to Formula II:

(II)

(SEQ ID NO: 2)

Xaa1-Ile-Pro-Xaa2-Leu-Tyr-Xaa3-Phe-Ala-Xaa4

wherein the C-terminal amino acid is optionally amidated, or a salt thereof.

9. The compound of claim 1 , or a salt thereof, wherein said compound is selected from a group consisting of

(SEQ ID NO: 3)

D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser;

(SEQ ID NO: 4)

D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-β-

Ala;

(SEQ ID NO: 5)

D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-β-

AlaNH 2 ;

and

(SEQ ID NO: 6)

D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-

NH 2 ;

or a salt thereof.

10. A method of treating an individual suffering from a cellular proliferative disorder, comprising administering to the individual an effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cellular proliferative disorder is selected from the group consisting of hemangiomatosis in newborn, secondary progressive multiple sclerosis, atherosclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget's disease of the bone, fibrocystic disease of the breast, uterine fibroids, Peyronie's disease, Dupuytren's disease, restenosis, benign proliferative breast disease, benign prostatic hyperplasia, X linked lymphocellular proliferative disorder, post transplantation lymphocellular proliferative disorder, macular degeneration, retinopathies, proliferative vitreoretinopathy and non-cancerous lymphocellular proliferative disorders.

11. A method of treating an individual suffering from a cancer, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, colorectal cancer, brain cancer, endometrial cancer, liver cancer, stomach cancer and leukemia, comprising administering to the individual an effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 wherein said leukemia is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia and chronic lymphoid leukemia.

13. The method according to claim 11 wherein the cancer is selected from the group consisting of breast cancer and glioblastoma.