US 5,849,695 AGranted

Parathyroid hormone analogues useful for treatment of osteoporosis and disorders of calcium meatabolism in mammals

AssigneeThe Regents of the University of California

InventorsFred E. Cohen, Robert A. Nissenson, Gordon J. Strewler

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Abstract

The present invention relates polypeptide analogs which have agonist or antagonist or tissue selection properties relative to parathyroid hormone (PTH), parathyroid hormone-like protein (PLP) or parathyroid-related protein (PTHrP). The serine amino acid at position 3, the glutamine amino acid at position 6, the histidine amino acid at position 9 or combinations thereof are substituted by other natural or synthetic amino acids. Preferably, a human PTH fragment of about 34 amino acids is sufficient for pharmacological activity. These polypeptides are useful as agonists or antagonists in the treatment of a human being for disease conditions of cancer, osteoporosis, hypercalcemia, or hyperparathyroid disease conditions. The invention also concerns a method of performing certain assays using the modified peptides, and based on the results of the assays falling within preset limits, selecting those modified peptides which shall be useful in the treatment of disease conditions.

Claims29

Dependent claims

A pharmaceutical composition useful in the treatment of disease conditions of bone in a mammal comprising a peptide analog compound of the formula:

H.sub.2 N-(Ser or Ala).sup.1 -Val-B.sup.3 -Glu-Ile-J.sup.6 -(Leu or Phe).sup.7 -Met-X.sup.9 -Asn.sup.10- -Leu-Gly-Lys-His--Leu-(Asn or Ser).sup.16 -Ser-(Met or Leu).sup.18 -Glu-Arg.sup.20 -Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln--Asp.sup.30 -Val-His-Asn-Phe.sup.34 -Z (Structure I), or
the pharmaceutically acceptable salts thereof, wherein:
the amino acid B at position 3 is independently selected from L-serine or those other natural or synthetic L-amino acids having a spatial volume comparable to or greater than serine provided that the amino acid B is not glycine or Glu,
the amino acid J at position 6 is independently selected from L-glutamine or from other natural or synthetic L amino acids,
the amino acid X at position 9 is independently selected from L-histidine or from other natural or synthetic amino acids,
with the proviso that when group B is L-serine, and J is L-glutamine, group X is not L-histidine, when group B is L-serine and group X is L-histidine, group J is not L-glutamine, and when group J is L-glutamine and group X is histidine, group B is not L-serine, and
Z is independently selected from -COOH, -COO-+M wherein +M is selected from pharmaceutically acceptable cations, -(C.dbd.O)NH.sub.2, or the sequence of amino acids of human, bovine or porcine parathyroid hormone (35-84) or human, bovine or porcine parathyroid hormone-related protein (PTHrP) (35-141);
wherein
said peptide analog compound has a low binding and a low activity in specific soft renal tissue as compared to the reference compound bPTH(1-34), and a high specific bone cell binding and a high activity compared to the activity of said peptide analog compound in soft renal tissue, with the proviso that specific bone cell excludes soft bone marrow cells.

6 more elements

A pharmaceutical composition useful in the treatment of disease conditions of bone in a mammal comprising a peptide analog compound independently selected from:

H.sub.2 N-Ser-Val-Lys-A';
H.sub.2 N-Ser-Val-Phe-A';
H.sub.2 N-Ser-Val-Leu-A';
H.sub.2 N-Ser-Val-Ala-A';
H.sub.2 N-Ser-Val-Thr-A';
H.sub.2 N-Ser-Val-Cys-A';
H.sub.2 N-Ser-Val-Tyr-A';
H.sub.2 N-Ser-Val-Asp-A';
H.sub.2 N-Ser-Val-Asn-A';
H.sub.2 N-Ser-Val-Gln-A';
H.sub.2 N-Ser-Val-Lys-A';
H.sub.2 N-Ser-Val-Arg-A';
H.sub.2 N-Ser-Val-His-A';
H.sub.2 N-Ser-Val-Val-A';
H.sub.2 N-Ser-Val-Ile-A';
H.sub.2 N-Ser-Val-Trp-A';
H.sub.2 N-Ser-Val-Met-A';
H.sub.2 N-Ser-Val-Pro-A';
H.sub.2 N-Ser-Val-Nle-A';
H.sub.2 N-Ser-Val-Orn;
H.sub.2 N-Ala-Val-Ala-A';
H.sub.2 N-Ala-Val-Thr-A';
H.sub.2 N-Ala-Val-Cys-A';
H.sub.2 N-Ala-Val-Tyr-A';
H.sub.2 N-Ala-Val-Asp-A';
H.sub.2 N-Ala-Val-Asn-A';
H.sub.2 N-Ala-Val-Gln-A';
H.sub.2 N-Ala-Val-Lys-A';
H.sub.2 N-Ala-Vai-Arg-A';
H.sub.2 N-Ala-Val-His-A';
H.sub.2 N-Ala-Val-Val-A';
H.sub.2 N-Ala-Val-Leu-A';
H.sub.2 N-Ala-Val-Nle-A';
H.sub.2 N-Ala-Val-Pro-A';
H.sub.2 N-Ala-Val-Phe-A';
H.sub.2 N-Ala-Val-Trp-A';
H.sub.2 N-Ala-Val-Met-A';
H.sub.2 N-Ala-Val-Ile-A';
or
H.sub.2 N-Ala-Val-Orn-A';
where A'is selected from the 4-34 amino acid sequence for human PTH or bovine PTH or their Z.dbd.--COOH or --COO--+M, wherein M is a pharmaceutically acceptable cation or --(C.dbd.O)NH.sub.2 derivatives, or the 4-84 sequence of hPTH, bPTH, or pPTH or hPTHrP;
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Thr-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Cys-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Tyr-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Asp-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Glu-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Asn-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Ser-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Lys-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Arg-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-His-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Val-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Leu-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Ile-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Pro-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Phe-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Trp-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Met-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gly-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Nle-B';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Orn-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Ala-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Thr-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Cys-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Tyr-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Asp-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Glu-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Asn-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Ser-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Lys-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Arg-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-His-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Val-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Leu-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Ile-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Pro-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Phe-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Trp-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Met-B';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gly-B';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Phe-B';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Nle-B';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Orn-B';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Ser-B';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Phe-B';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Ser-B';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-His-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-Leu-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-Lys-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-His-Glu-Ile-GIu-B';
H.sub.2 N-Ser-Val-Leu-Glu-Ile-Glu-B';
H.sub.2 N-Ser-Val-Lys-Glu-Ile-Glu-B';
H.sub.2 N-Ala-Val-Phe-Giu-Ile-Phe-B'
H.sub.2 N-AIa-Val-Phe-Glu-Ile-Ser-B';
H.sub.2 N-Ala-Val-Val-Glu-Ile-Phe-B';
H.sub.2 N-Ala-Val-Tyr-Glu-Ile-Phe-B';
H.sub.2 N-Ala-Val-Tyr-Glu-Ile-Ser-B';
H.sub.2 N-Ala-Val-Phe-Glu-Ile-Ala-B';
H.sub.2 N-AIa-Val-Lys-GIu-Ile-Ala-B';
H.sub.2 N-Ala-Val-His-Glu-Ile-Ala-B';
H.sub.2 N-Ser-Val-His-GIu-Ile-Ala-B';
or
H.sub.2 N-Ser-Val-Leu-Glu-Ile-Ala-B';
wherein Group B'is selected from the remainder of the remaining peptides of 7-34 active unit of hPTH, bPTH, or pPTH, or their Z.dbd.COOH or COO--+M or --(C.dbd.O)NH.sub.2 derivatives, or the 7-84 sequence of hPTH or bPTH or hPTrH;
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Gln-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Ser-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Phe-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Ser-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Gln-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Ser-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Phe-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Phe-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Tyr-Glu-Ile-Nle-Leu-Met-His-D';
or
H.sub.2 N-Ser-Val-Phe-Glu-Ile-Orn-Leu-Met-His-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Ala-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Ser-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Leu-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gin-Leu-Met-Phe-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Tyr-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gin-Leu-Met-Glu-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Lys-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Gln-D';
H.sub.2 N-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-Nle-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Ala-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Ser-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Leu-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Phe-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Tyr-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Glu-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Lys-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Gln-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Nle-D';
or
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Gln-Phe-Met-Orn-D';
H.sub.2 N-Ala-Val-Phe-Glu-Ile-Gln-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Phe-Glu-Ile-Ser-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Phe-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Ser-Glu-Ile-Ser-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Tyr-Glu-Ile-Gln-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Tyr-Glu-Ile-Ser-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Phe-Glu-Ile-Phe-Phe-Met-His-D';
H.sub.2 N-Ala-Val-Tyr-Glu-Ile-Phe-Phe-Met-His-D';
or
H.sub.2 N-Ala-Val-Nle-Glu-Ile-Phe-Phe-Met-His-D'
or the pharmaceutically acceptable salts thereof, wherein D'is selected from the 10-34 amino acid sequence for human or bovine PTH or their Z.dbd.--COOH or COO--+M or --(C.dbd.O)NH.sub.2 derivatives, or the remaining 10-84 sequence of pPTH, bPTH, pPTH or hPTHrP in combination with a pharmaceutically acceptable excipient;
wherein said peptide analog compound has a low binding and a low activity in specific soft renal tissue as compared to the reference compound bPTH(1-34), and a high specific bone cell binding and a high activity compared to the activity of said peptide analog compound in soft renal tissue, with the proviso that bone cells excludes soft bone marrow cells.

146 more elements

Dependencies are inferred from the claim text.