Peptide analogs of alpha-melanocyte stimulating hormone

Patent metadata

Field	Value
Publication number	US-9738698-B2
Application number	US-201514830572-A
Country	US
Kind code	B2
Filing date	Aug 19, 2015
Priority date	May 27, 2008
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Provided herein are stable peptide analogs of the native alpha-melanocyte stimulating hormone (α-MSH) having selectivity for the melanocortin 1 receptor (MC1R). Also provided herein are pharmaceutical preparations of the α-MSH peptide analogs, as well as methods of using these analogs in the treatment of medical and veterinary conditions involving MC1R.

First claim

The invention claimed is:

1. A polypeptide comprising the sequence set forth in:
Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 ,
wherein Xaa 1 is D-Val, D-Ala, or D-Lys;
Xaa 2 is D-Pro, D-Ala, or D-Lys;
Xaa 3 is D-Lys, D-Orn, D-Nle, or D-Ala;
Xaa 4 is Gly, or D-Ala;
Xaa 5 is D-Trp, Trp, D-3-benzothienyl-Ala, D-5-hydroxy-Trp, D-5-methoxy-Trp, D-Phe, or D-Ala;
Xaa 6 is D-Arg, D-His, or D-Ala;
Xaa 7 is D-Cha, D-Phe, Phe, D-4-fluoro-Phg, D-3-pyridyl-Ala, D-Thi, D-Trp, D-4-nitro-Phe, or D-Ala;
Xaa 8 is D-His, His, D-Arg, Phe, or D-Ala;
Xaa 9 is D-Glu, D-Asp, D-citrulline, D-Ser, or D-Ala;
Xaa 10 is D-Met, D-buthionine, D-Ile, or D-Ala;
Xaa 11 is D-Ser, D-Ile, or D-Ala;
Xaa 12 is D-Tyr, D-Ser, or D-Ala; and
Xaa 13 is D-Ser or D-Ala;

wherein:
no more than one of Xaa 1-13 is D-Ala except when Xaa 1-3 are all D-Ala, and,
no more than one of Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof.

2. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein at least one of Xaa 1-13 is D-Ala except when Xaa 1-3 are all D-Lys.

3. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , said polypeptide comprising a core tetrapeptide having the sequence:
D-Trp D-Arg Xaa D-His (SEQ ID NO: 2),
wherein Xaa is D-Cha, D-Phe, or Phe.

4. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , said polypeptide comprising a C-terminal polypeptide having the sequence: D-Ser D-Ile D-Ile D-Ser D-Ser (SEQ ID NO: 3).

5. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , said polypeptide comprising the sequence set forth in:

(SEQ ID NO: 34)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ala;

(SEQ ID NO: 35)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Ala D-Ser;

(SEQ ID NO: 36) 

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ala D-Tyr D-Ser;

(SEQ ID NO: 37) 

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Ala D-Ser D-Tyr D-Ser;

(SEQ ID NO: 38) 

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Ala

D-Met D-Ser D-Tyr D-Ser;

(SEQ ID NO: 43) 

D-Val D-Pro D-Lys D-Ala D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser;

(SEQ ID NO: 44) 

D-Val D-Pro D-Ala Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser;

(SEQ ID NO: 45) 

D-Val D-Ala D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser;

(SEQ ID NO: 46) 

D-Ala D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser;

(SEQ ID NO: 47) 

D-Ala D-Ala D-Ala Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser;

or

(SEQ ID NO: 48)

D-Lys D-Lys D-Lys Gly D-Trp D-Arg D-Phe D-His D-Glu

D-Met D-Ser D-Tyr D-Ser.

6. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said polypeptide is PEGylated.

7. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said polypeptide exhibits at least one of the following properties:
ability to selectively activate melanocortin 1 receptor (MC1R);
stability in plasma in vitro; or
resistance to protease degradation.

8. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said polypeptide is conjugated to a biologically active moiety.

9. A pharmaceutical composition comprising the polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

10. A composition for treating an autoimmune disease or condition in a subject in need thereof, comprising a therapeutically effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient,
wherein said autoimmune disease or condition is selected from the group consisting of multiple sclerosis, diabetes type I, aplastic anemia, Grave's disease, coeliac disease, Crohn's disease, lupus, arthritis, osteoarthritis, autoimmune uveitis, and myasthenia gravis.

11. A composition for treating inflammation in a subject in need thereof, comprising a therapeutically effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient,
wherein said inflammation is associated with a disease selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, allergy, atherosclerosis, psoriasis, gastritis, and ischemic heart disease.

12. A composition for reducing or inhibiting transplant rejection in a subject in need thereof, comprising a therapeutically effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

13. A composition for treating melanoma in a subject in need thereof, comprising a therapeutically effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

14. A composition for treating melanom

Assignees

• Genzyme Corp

Inventors

• Perricone Michael A
• Dzuris John Lyle
• Weeden Timothy E
• Stefano James E
• Pan Clark Q
• Edling Andrea E

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title