Peptide derivatives having vasodilating activity

Details Peptide derivatives having vasodilating activity Peptide derivatives having vasodilating activity

1991-10-17

1994-04-26

Lee, Lester L.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

C07K 710

Patent

active

053068084

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to novel endothelin derivatives which are expected to be useful as therapeutic drugs such as agents for improving circulatory functions (for example, therapeutic agents for hypertension or hypotension), therapeutic agents for cardiac or cerebral circulatory diseases (for example, cardiac infarction), and therapeutic agents for renal diseases (for example, acute renal insufficiency); methods for producing the same; and agents for improving circulatory functions mainly comprising the same.
Endothelin (ET) is a vasoconstrictive peptide composed of 21 amino acid residues which was isolated from the culture supernatant of the endothelial cells of porcine aortas and whose structure was determined by M. Yanagisawa et al. in 1988 [M. Yanagisawa et al., Nature 332, 411-415 (1988)]. After that, the research on genes coding for endothelin revealed the presence of peptides similar to endothelin in structure. These peptides are named endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), respectively, and their structures are as follows: ##STR2## (All of the amino acids constituting ET-1, ET-2 and ET-3 take the L-form.) (Inoue et al., Proc. Natl. Acad. Sci. U.S.A. 86, 2863-2867)
The above-mentioned peptides of the endothelin family exist in vivo and have vasopressor activity. For this reason, these peptides are anticipated to be intrinsic factors responsible for the control of circulatory systems, and deduced to be related to hypertension, cardiac or cerebral circulatory diseases (for example, cardiac infarction) and renal diseases (for example, acute renal insufficiency).
If antagonists or agonists of the above-mentioned peptides are obtained, they are considered not only useful for elucidation of the functional mechanism of these peptides, but also they are most likely to be used as effective therapeutic drugs for these diseases. At present, however, no reports are found that an effective antagonist to endothelin has been obtained. Further, it is another subject of the present invention to discover a substance which enhances the activity of endothelin.


SUMMARY OF THE INVENTION

The present inventors conducted intensive investigation, using the action of suppressing or enhancing strong vascular smooth muscle constrictor activity due to endothelin as an indication, and synthesized endothelin analogues by the replacement of amino acids of endothelin. As a result, the present inventors found that novel endothelin derivatives of the present invention had the antagonist action or the agonist action to endothelin, thus completing the present invention.
Namely, the present invention provides
(1) a peptide derivative represented by general formula [I] or a pharmaceutically acceptable salt thereof: ##STR3## wherein A, B, C, D, E and F each represent amino acid residues, and satisfy any one condition of (i) A=Ser, B=Ser, C=Ser, D=Leu, E=Met and, F=Phe (SEQ. ID NO:4), (ii) A=Ser, B=Ser, C=Ser, D=Trp, E=Leu and F=Phe (SEQ. ID NO:5) , and (iii) A=Thr, B=Phe, C=Thr, D=Tyr, E=Lys and F=Tyr (SEQ. ID NO.6); and W, X, Y and Z each represent amino acid residues, and satisfy any one condition of (i) at least one of W and Y is an amino acid residue other than an L-alanine residue or other than an L-cysteine residue, (ii) X is an amino acid residue other than an L-lysine residue, and (iii) Z is an amino acid residue other than an L-aspartic acid residue;
(2) a method for producing the peptide derivative represented by general formula [I] or the salt thereof, which comprises subjecting a peptide derivative represented by general formula [II]or a salt thereof to oxidation reaction: any one condition of (i) A=Ser, B=Ser, C=Ser, D=Leu, E=Met and F=Phe, (ii) A=Ser, B=Ser, C=Ser, D=Trp, E=Leu and F=Phe, and (iii) A=Thr, B=Phe, C=Thr, D=Tyr, E=Lys and F=Tyr; and W, X, Y and Z each represent amino acid residues, and satisfy any one condition of (i) at least one of W and Y is an amino acid residue other than an L-alanine residue or other than an L-cysteine residue, (ii) X is an

REFERENCES:
Inoue, A. et al. PNAS 86; 2863-2867; Apr. 1989.
Randall, M. D. et al. Br. J. Pharmacol. 98; 685-699 (1989).

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