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Last Updated: September 22, 2020

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Claims for Patent: 5,589,452

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Summary for Patent: 5,589,452
Title: Analogs of parathyroid hormone and parathyroid hormone related peptide: synthesis and use for the treatment of osteoporosis
Abstract:Synthetic polypeptide analogs of parathyroid hormone PTH, parathyroid hormone related peptide PTHrp, and of the physiologically active truncated homologs and analogs of PTH and PTHrp, in which amino acid residues (22-31) form an amphipathic .alpha.-helix, said residues (22-31) selected from hydrophilic amino acids (Haa) and lipophilic amino acids (Laa) ordered in the sequence: and their pharmaceutically acceptable salts are useful for the prophylaxis and treatment of ostoporosis in mammals. Processes for the production of the polypeptides via solid phase and recombinant methods are provided.
Inventor(s): Krstenansky; John L. (Palo Alto, CA), Nestor, Jr.; John J. (Cupertino, CA), Ho; Teresa H. (Los Altos, CA), Vickery; Brian H. (Mountain View, CA), Bach; Chinh T. (San Jose, CA)
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Application Number:07/915,247
Patent Claims:1. A modified parathyroid honnone related polypeptide (PTHrP), of the formula:

Ala Val Ser Glu Xaa.sup.5 Gln Leu Leu His Asp Xaa.sup.11 Gly Xaa.sup.13 Ser Ile

Gln Asp Leu Xaa.sup.19 Arg Xaa.sup.21 Xaa.sup.22-31 Xaa.sup.32 Xaa.sup.33 Xaa.sup.34 Term, wherein:

Xaa.sup.5 is His or Ala;

Xaa.sup.11 and Xaa.sup.13 are independently Lys, Arg, or Leu;

Xaa.sup.19 and Xaa.sup.21 are independently Ala or Arg;

Xaa.sup.22-31 is selected from the group consisting of (SEQ ID NOS: 26, 27, 28, 29, and 30);

Xaa.sup.32 is His or Lys;

Xaa.sup.33 is Thr, Glu, or Ala;

Xaa.sup.34 is Ala, hSer, Tyr, or Leu;

Term is OH, NR.sub.2, lactone, or Gly Arg Arg, where R is H or (C.sub.1 -C.sub.4) alkyl; and the pharmaceutically acceptable salts thereof.

2. A polypeptide of claim 1 wherein Xaa.sup.22-31 is (SEQ ID NO:26).

3. A polypeptide of claim 2 wherein Xaa.sup.11 and Xaa.sup.13 are both Lys; and Xaa.sup.19 and Xaa.sup.21 are both Arg.

4. The polypeptide of claim 3 which is: ##STR16##

5. The polypeptide of claim 3 which is: ##STR17##

6. The polypeptide of claim 3 which is: ##STR18##

7. The polypeptide of claim 3 which is: ##STR19##

8. The polypeptide of claim 3 which is: ##STR20##

9. The polypeptide of claim 3 which is: ##STR21##

10. The polypeptide of claim 3 which is: ##STR22##

11. A polypeptide of claim 2 wherein Xaa.sup.11 and Xaa.sup.13 are both Lys; and one of Xaa.sup.19 and Xaa.sup.21 is Arg and the other is Ala.

12. The polypeptide of claim 11 which is: ##STR23##

13. The polypeptide of claim 11 which is: ##STR24##

14. A polypeptide of claim 2 wherein one of Xaa.sup.11 and Xaa.sup.13 is Leu and the other is Lys; and Xaa.sup.19 and Xaa.sup.21 are both Arg.

15. The polypeptide of claim 14 which is: ##STR25##

16. A polypeptide of claim 1 wherein Xaa.sup.22-31 is (SEQ ID NO:27).

17. A polypeptide of claim 16 wherein Xaa.sup.11 and Xaa.sup.13 are both Lys or both Arg; and Xaa.sup.19 and Xaa.sup.21 are both Arg.

18. The polypeptide of claim 17 which is: ##STR26##

19. The polypeptide of claim 17 which is: ##STR27##

20. The polypeptide of claim 17 which is: ##STR28##

21. The polypeptide of claim 17 which is: ##STR29##

22. The polypeptide of claim 17 which is: ##STR30##

23. A polypeptide of claim 1 wherein Xaa.sup.22-31 is (SEQ ID NO:28).

24. The polypeptide of claim 23 which is: ##STR31##

25. A polypeptide of claim 1 wherein Xaa.sup.22-31 is (SEQ ID NO:29).

26. The polypeptide of claim 25 which is: ##STR32##

27. A polypeptide of claim 1 wherein Xaa.sup.22-31 is (SEQ ID NO:30).

28. A polypeptide of claim 27 which is: ##STR33##

29. A polypeptide of claim 1 produced by a process of solid phase synthesis, which process comprises sequentially coupling protected amino acids on a suitable resin support, removing the side chain and N.sup..alpha. protecting groups, and cleaving the polypeptide from the resin support.

30. A polypeptide of claim 1 produced by expressing a gene encoding said polypeptide.

31. A modified parathyroid hormone (PTH) polypeptide, of the formula:

Xaa.sup.1 Val Ser Glu Ile Gln Xaa.sup.7 Xaa.sup.8 His Asn Leu Gly Lys His Leu

Xaa.sup.16 Ser Xaa.sup.18 Xaa.sup.19 Arg Xaa.sup.21 Xaa.sup.22-31 His Asn Xaa.sup.34 Term, wherein:

Xaa.sup.1 is Ser or Ala;

Xaa.sup.7 is Leu or Phe;

Xaa.sup.8 is Met or Nle;

Xaa.sup.16 is Asn or Ser;

Xaa.sup.18 is Leu, Met, or Nle;

Xaa.sup.19 is Glu or Arg;

Xaa.sup.21 is Val or Arg;

Xaa.sup.22-31 is selected from the group consisting of (SEQ ID NOS: 26, 27, 28, 29, and 30);

Xaa.sup.34 is Phe or Tyr;

Term is OH or NR.sub.2, where R is H or (C.sub.1 -C.sub.4) alkyl; and the pharmaceutically acceptable salts thereof.

32. A pharmaceutical composition for the prevention or treatment of conditions characterized by decreases in bone mass comprising an effective bone mass increasing amount of a polypeptide of claim 31, or salt thereof, and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition in unit dosage form, for treating conditions characterized by decreases in bone mass, comprising from about 0.5 .mu.g to about 50 .mu.g of a polypeptide of claim 31, or salt thereof, and a pharmaceutically acceptable carrier.

34. The polypeptide of claim 1 which is: ##STR34##

35. The polypeptide of claim 31 which is: ##STR35##

36. A polypeptide of claim 31 produced by a process of solid phase synthesis, which process comprises sequentially coupling protected amino acids on a suitable resin support, removing the side chain, and N.sup..alpha. protecting groups, and cleaving the polypeptide from the resin support.

37. A polypeptide of claim 31 produced by expressing a gene encoding said polypeptide.

Details for Patent 5,589,452

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23   Start Trial Syntex (U.S.A.) Inc. (Palo Alto, CA) 2039-02-26 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Start Trial Syntex (U.S.A.) Inc. (Palo Alto, CA) 2039-02-26 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Start Trial Syntex (U.S.A.) Inc. (Palo Alto, CA) 2039-02-26 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23   Start Trial Syntex (U.S.A.) Inc. (Palo Alto, CA) 2039-02-26 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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