Endothelin-antagonizing peptide

Details Endothelin-antagonizing peptide Endothelin-antagonizing peptide

1995-02-10

1997-05-20

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 11, 530317, 530326, A61K 3800, C07K 708, C07K 512

Patent

active

056312229

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/01011 filed Jun. 23, 1994.


TECHNICAL FIELD

The present invention relates to a novel peptide which has endothelin-antagonizing activity. The peptide has excellent endothelin-antagonizing activity, and is therefore useful for treatment of hypertension, asthma, cerebral apoplexy, angina pectoris, actute renal insufficiency, cardiac infarction, cerebral vasospasm, etc.


BACKGROUND ART

Endothelin is a cyclic peptide which possesses a strong, long-lasting vasoconstricting effect, and is thought to be one of the substances responsible for hypertension, asthma, cerebral apoplexy, angina pectoris, actute renal insufficiency, cardiac infarction, and cerebral vasospasm. Consequently, a substance which antagonizes endothelin and inhibits its effects is expected to be useful for the treatment and prevention of these diseases.
It is known that the cyclic peptide represented by the following formula (A) exhibits the endothelin antagonism (Japanese Published Unexamined Patent Application No. 130299/91): ##STR1## (wherein U represents D-Val or D-allo-Ile, R.sup.A represents hydrogen or an amino-protective group, and R.sup.B represents hydrogen or a carboxy-protective group). Related cyclic peptides BE-18257 derivatives and BQ-123 derivatives have also been reported (Japanese Published Unexamined Patent Application No. 94692/91, U.S. Pat. No. 5,114,918). ##STR2##
Cyclodepsipeptides represented by the following formula have been reported as cyclic peptides containing abnormal amino acid [Cochinmicins; J. Antibiotics, 45, 1709-1722 (1992)]. ##STR3##


______________________________________ Cochinmicin X * ______________________________________ 1 I H R 2 II Cl S 3 III Cl R ______________________________________
Olygopeptides represented by the following formula have also been reported as other peptides having the endothelin-antagonizing activity [EP-A-0457195, J. Pharm. Exp. Ther., 264, 1040-1046 (1992)]. ##STR4##
The similar peptides represented by the following formula have further been reported (Abstract of the 65th Conference of Biochemical Society of Japan, p 769) ##STR5##
There have been many reports on endothelin derivatives and partial peptides of endothelin [WO91-13089, Japanese Published Unexamined Patent Application No. 59098/93, WO 92-02237, J. Med. Chem., 35, 3301-3303 (1992), Biochem. Biophys. Res. Commun., 179, 286-292 (1991), Biochem. Biophys. Res. Commun., 184, 953-959 (1992), FEBS Lett., 311, 12-16 (1992), Biochem. Biophys. Res. Commun., 184, 100-106 (1992), Biochem. Biophys. Res. Commun., 183, 566-571 (1992), Proc. Natl. Acad. Sci. U.S.A., 88, 7443-7446 (1991), J. Pharm. Exp. Ther., 260, 632-636 (1992), EP-A-499266, etc].
There have also been reports on random modification of C-terminal peptides of endothelin-1 [BioMed. Chem. Lett., 3. 497-502 (1993), BioMed. Chem. Lett., 3, 519-524 (1993)].


DISCLOSURE OF THE INVENTION

According to the present invention, there is provided a peptide compound represented by the following formula (I): -R.sup.9 -R.sup.10 -R.sup.11 -R.sup.12 -Phe-R.sup.14 -R.sup.15 -R.sup.16 -R.sup.17 -R.sup.18 -Ile-R.sup.20 -Z (SEQ ID NO.: 64) (I) ##STR6## or hydrogen; R.sup.2 represents Asn, Asp, Phe, Tyr, Ser, or a single bond; ##STR7## or a single bond; R.sup.10 represents Trp or Ala; or Nle; t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or carboxy-substituted or unsubstituted lower alkanoyl; X.sup.2 represents hydrogen or acetamidomethyl; Y.sup.1 represents hydroxy or lower alkoxy; Y.sup.2 represents hydrogen; or X.sup.1 and Y.sup.1 or X.sup.2 and Y.sup.2 are combined together to form a single bond as X.sup.1 -Y.sup.1 or X.sup.2 -Y.sup.2 ; and Nva represents a norvaline residue, Cha represents a .beta.-cyclohexylalanine residue, Abu represents a 2-aminobutanoic acid residue, Thi represents a .beta.-(2-thienyl)alanine residue, Phg represents a phenylglycine residue, Nle represents a norleucine residue, MeAla represents a N-methylalanine residue, MeLeu represents a N-methylleucine residue, Melle represents a N-methylisoleucine resid

REFERENCES:
patent: 5231166 (1993-07-01), Masaki et al.
patent: 5294569 (1994-03-01), Masaki et al.
patent: 5306808 (1994-04-01), Wakimasu et al.
patent: 5352659 (1994-10-01), Wakimasu et al.
patent: 5382569 (1995-01-01), Cody et al.

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