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Last Updated: March 28, 2024

Claims for Patent: 5,695,955


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Summary for Patent: 5,695,955
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, these 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:08/448,070
Patent Claims:1. A process for the synthesis of a modified parathyroid hormone 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; and

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, which process comprises expressing a nucleic acid sequence encoding said polypeptide.

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

3. A process of claim 2 wherein said polypeptide is selected from the group consisting of (SEQ ID NOS: 7, 8 and 9).

4. A process of claim 1 wherein said polypeptide comprises a polypeptide wherein Xaa.sup.22-31 is (SEQ ID NO:27).

5. A process of claim 1 wherein said polypeptide comprises a polypeptide wherein Xaa.sup.22-31 is (SEQ ID NO:28).

6. A process of claim 1 wherein said polypeptide comprises a polypeptide wherein Xaa.sup.22-31 is (SEQ ID NO:29).

7. A process of claim 1 wherein said polypeptide comprises a polypeptide wherein Xaa.sup.22-31 is (SEQ ID NO:30).

8. A process for the synthesis of 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 Ash 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 Ash 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 (SEQ ID NOS: 26, 27, 28, 29, or 30);

Xaa.sup.34 is Phe or Tyr; and Term is OH or NR.sub.2, where R is H or a (C.sub.1 -C.sub.4)alkyl; and the pharmaceutically acceptable salts thereof, which process comprises expressing a nucleic acid sequence encoding said polypeptide.

9. An expression vector comprising a nucleic acid sequence encoding a PTHrP analog 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; and

Term is OH, NR.sub.2, lactone, or Gly Arg Arg, where R is H or (C.sub.1 -C.sub.4) alkyl.

10. A host cell transformed with an expression vector of claim 9.

11. An expression vector encoding 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 Set;

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 (SEQ ID NOS: 26, 27, 28, 29, or 30);

Xaa.sup.34 is Phe or Tyr; and Term is OH or NR.sub.2, where R is H or a (C.sub.1 -C.sub.4)alkyl.

12. A host cell transformed with an expression vector of claim 11.

13. The polypeptide of SEQ ID NO: 26.

14. The polypeptide of SEQ ID NO: 27.

15. The polypeptide of SEQ ID NO: 28.

16. The polypeptide of SEQ ID NO: 29.

17. The polypeptide of SEQ ID NO: 30.

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