Peptide derivatives

Details Peptide derivatives Peptide derivatives

1991-12-11

1993-10-12

Wityshyn, Michael G.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

25 or more amino acid residues in defined sequence

A61K 3702, C07K 710

Patent

active

052527050

DESCRIPTION:

BRIEF SUMMARY
FIELD OF ART

The present invention relates to novel peptide derivatives. In more particular, it relates to parathyroid hormone antagonists.


BACKGROUND OF THE INVENTION

Parathyroid hormone (referred to as PTH hereinafter) is a peptide hormone consisting of 84 amino acid residues, which is responsible for bone and calcium metabolism. A peptide fragment consisting of the first to 34th amino acid residues at the N-terminal of PTH, which is called PTH (1-34), has the same biological activity as PTH. On the other hand, other peptide fragments which lack the first few N-terminal amino acid residues, PTH (3-34), PTH (7-34), and the like, are known to suppress PTH activity.
Recently, it has been found that a PTH-related peptide (referred to as PTHrP hereinafter) derived from human carcinoma exhibits biological activity similar to PTH, and its chemical structure has been determined (Suva et al, Science, Vol.237, 893, 1987). The human PTHrP is a polypeptide consisting of 141 amino acid residues. It has biological activity similar to that of PTH, such as elevation of blood calcium level, acceleration of born absorption, lowering of blood phosphorous level, lowering of urinary calcium level, increasing of urinary cAMP level, and activation of hydroxylase at the 1-position of vitamin D in kidney (Horiuchi et al, Science, Vol.238, 1988; Kemp et al, Science, Vol.238, 1988).
Primary structure of PTHrP has poor similarity to that of PTH although partial structure of PTHrP at the amino terminal shows similarity to that of PTH. In spite of the fact, fragments of PTHrP, which lack a few amino terminal residues, such as PTHrP (3-34), suppress PTH activity likewise in PTH (Rabbani et al, oral speech at the meeting of the America Bone Metablism Association, 1988).
PTH derivatives such as [Tyr.sup.34 ]-hPTH (3-34)-NH.sub.2 and PTHrP derivatives such as hPTHrP (3-34)-NH.sub.2 are known as a PTH antagonist. However, there has been a need to discover move potent PTH antagonist activity. The present invention relates to the peptides consisting of 25-50 amino acid residues and comprising the following peptide sequence, and amides and salts thereof. -His-Leu-Ile-Ala-Glu-Ile (Seq Id No. 1) (I)
The peptide derivatives of the present invention contain at least the peptide sequence represented by the formula (I) mentioned above. For instance, the peptide derivatives of the invention may be represented by the following formula (II): is-His-Leu-Ile-Ala-Glu-Ile-Y-z (II) H-A-Gln, (Seq. ID Nos. 6-9) H-Glu-A-Gln- (Seq. Id. Nos: 14-17), or Ser-Glu-A-Gln- (Seq. ID Nos: 18-21), wherein A is Ile, Thr, Val, or Leu; Y represents His-Thr-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala-Thr-Ser-Glu-Val, His-Thr-Ala-Glue-Ile-Arg-Ala-Thr-Ser-Glu-Val-Ser-Pro-Asn-Ser-Lys-Pro-Asn; Z represents OH or NH.sub.2.
The following Table 1 lists specific examples of the peptide derivatives of the invention.


TABLE 1 __________________________________________________________________________ X--Leu--Met--His--Asn--Leu--Gly--Lys--Ser--Ile--Gln--Asp--Leu--Arg--Arg-- Arg--Phe--Phe--Leu--His--His--Leu--Ile--Ala--Glu--Ile--Y--Z Compound No. X Y Z __________________________________________________________________________ 1 H--Ser--Glu--Ile--Gln His--Thr--Ala NH.sub.2 (SEQ ID NO: 18) 2 H--Glu--Ile--Gln His--Thr--Ala NH.sub.2 (SEQ ID NO: 14) 3 H--Ile--Gln His--Thr--Ala NH.sub.2 (SEQ ID NO: 10) 4 H--Gln His--Thr--Ala NH.sub.2 (SEQ ID NO: 6) 5 H His--Thr--Ala NH.sub.2 (SEQ ID NO: 2) 6 H--Ser--Glu--Ile--Gln His--Thr--Ala OH (SEQ ID NO: 18) 7 H--Ser--Glu--Ile--Gln His--Thr--Ala--Glu-- NH.sub.2 (SEQ ID NO: 19) Ile--Arg--Ala 8 H--Ser--Glu--Ile--Gln His--Thr--Ala--Glu-- NH.sub.2 (SEQ ID NO:20) Ile--Arg--Ala--Thr-- Ser--Glu--Val 9 H--Ser--Glu--Ile--Gln His--Thr--Ala--Glu-- NH.sub.2 (SEQ ID NO: 21) Ile--Arg--Ala--Thr-- Ser--Glu--Val--Ser-- Pro--Asn--Ser--Lys-- Pro--Asn 10 H--Ser--Glu--Val--Gln His--Thr--Ala NH.sub.2 (SEQ ID NO: 18) 11 H--Ser--Glu--Thr--Gln His--Thr--Ala

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