Endothelin-antagonizing peptide

Details Endothelin-antagonizing peptide Endothelin-antagonizing peptide

2001-01-02

2003-11-04

Low, Christopher S. F. (Department: 1653)

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

C530S324000, C530S325000, C514S012200, C514S013800, C514S014800, C514S015800, C514S016700

Reexamination Certificate

active

06642355

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel peptide which has endothelin-antagonizing activity, and an intermediate for its synthesis. The peptide has excellent endothelin-antagonizing activity, and is therefore useful for treatment of hypertension, asthma, cerebral apoplexy, angina pectoris, acute renal failure, cardiac infarction, cerebral vasospasm, etc.
BACKGROUND OF THE INVENTION
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, acute renal failure, cardiac infarction, cerebral apoplexy, angina pectoris 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 formula (A):
(wherein U represents D-Val or D-allo-Ile, R
1
represents hydrogen or an amino-protective group, and R
2
represents hydrogen or a carboxyl-protective group) exhibits the endothelin antagonism (Japanese Published Unexamined Patent Application No. 130299/91).
DISCLOSURE OF THE INVENTION
The present inventors have made a screening of numerous substances produced by microorganisms in order to find a naturally occurring physiologically active substance having endothelin-antagonizing activity, have succeeded in isolating substances from the cultures of microorganisms belonging to the genus
Streptomyces
newly isolated from the soil, which substances have endothelin-antagonizing activity and a suppressing effect on the increase in intracellular calcium and intracellular guanosine-3′,5′-cyclic monophosphate concentrations due to endothelin, and have named the substances Compound (I-1), Compound (I-2) and Compound (I-3). As the result of further investigations, the present inventors have successfully determined the structure of these substances, have synthesized novel derivatives of these substances, and thus have completed the present invention.
According to the present invention, there is provided a peptide compound represented by the following formula (I):
X-A-Trp-B-Gly-Thr-E-G-Y   (I) SEQ ID NO. 2
wherein
A represents Asn or Asp;
B represents His or Lys;
E represents Ala or Ser;
G represents Ala or Pro;
X represents
Y represents hydroxy, lower alkoxy, amino,
wherein
each of X
1
and X
3
represents hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, or carbonyl-substituted or unsubstituted lower alkanoyl;
each of X
2
and Y
2
represents hydrogen;
Y
1
represents hydroxy, lower alkoxy or amino; or
X
1
and Y
1
, or X
2
and Y
2
are combined together to form a single bond as X
1
—Y
1
or X
2
—Y
2;
and
Z represents hydroxy, lower alkoxy, benzyloxy, benzhydryloxy, amino,
where
Z
2
is hydroxy, lower alkoxy, benzyloxy, benzhydryloxy or amino,
Gly—Z
1
where
Z
1
is hydroxy, lower alkoxy, benzyloxy, benzhydryloxy, amino,
where Z
2
is as defined previously, or Z
1
is combined with X
1
to form a single bond as X
1
-Z
1
,
Ala—Z
1
where Z
1
is as defined previously,
Val—Z
1
where Z
1
is as defined previously,
Trp—Z
1
where Z
1
is as defined previously,
Trp—Gly—Z
1
where Z
1
is as defined previously,
Trp-Asn-Tyr-Tyr-Trp-Z
1
where Z
1
is as defined previously,
 Trp-Phe-Phe-Asn-Tyr-Tyr-7Hyt-Z
1
,   SEQ ID NO: 4
where Z
1
is as defined previously, and 7Hyt represents 7-hydroxytryptophan,
Trp-Ile-Ile-Tr-Z
1
,   SEQ ID NO: 5
where Z
1
is as defined previously,
Trp-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp-Z
1
,   SEQ ID NO: 6
where Z
1
is as defined previously and W represents Ala, Ser or Cys,
Trp-W-His-Leu-Asp-Ile-Ile-Trp-Z
1
,   SEQ ID NO: 7
where Z
1
and W are as defined previously,
Trp-Val-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z
1
,   SEQ ID NO: 8
where Z
1
and W are as defined previously,
Trp-Leu-Tyr-Phe-W-His-Gln-Asp-Val-Ile-Trp-Z
1
,   SEQ ID NO: 9
where Z
1
and W are as defined previously,
Trp-Val-Tyr-Phe-W-Phe-Phe-Asn-Tyr-Tyr-Trp-Z
1
,   SEQ ID NO: 10
where Z
1
and W are as defined previously,
Trp-Phe-Phe-Asn-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z
1
,   SEQ ID NO: 11
where Z
1
is as defined previously,
Trp-Phe-Phe-Asn-Tyr-Tyr-Asn-Ile-Ile-Trp-Z
1
,   SEQ ID NO: 12
where Z
1
is as defined previously,
J-Phe-M-Q-Tyr-R-T-Z
1
,   SEQ ID NO: 13
where
J is Trp or a single bond,
M is Phe or a single bond,
Q is Asn or a single bond,
R is Tyr or a single bond,
T is
Trp,
Ala,
Phe,
Tyr,
Trp-Trp,
Asn-Tyr-Tyr-Trp,   SEQ ID NO: 14
Trp-Asn-Tyr-Tyr-Trp,   SEQ ID NO: 15
Try-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp,   SEQ ID NO: 16
where W is as defined previously, or a single bond,
2 or more of J, M, Q, R and T are not a single bond simultaneously, and Z
1
is as defined previously, or a pharmaceutically acceptable salt thereof.
Also, according to the present invention there is provided an intermediate represented by the following formula (II):
X
4
-J-Phe-M-Q-Tyr-R-T-Z
3
  (II) SEQ ID NO: 17
wherein X
4
represents hydrogen or benzyloxycarbolnyl, t-butyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, Z
3
represents hydroxy, lower alkoxy, benzyloxy or benzhydryloxy, and J, M, Q, R and T are as defined previously, which is useful for the synthesis of a peptide compound represented by the formula (I).
The peptide compound represented by the above formula (I) is referred to as Compound (I), and compounds represented by the other formulas are similarly referred to.
In the definitions for the above formulas (I) and (II), the lower alkyl and the alkyl moiety in lower alkoxy mean linear or branched alkyl having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and isohexyl. The lower alkanoyl means those having linear or branched 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl and pentanoyl.
As the pharmaceutically acceptable salt of Compound (I), mention may be made of an acid addition salt, a metal salt and an organic base addition salt. Specifically, the pharmaceutically acceptable acid addition salt includes, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, etc. and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, etc. The pharmaceutically acceptable metal salt includes, for example, alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as magnesium salt, calcium salt, etc., aluminum salt, zinc salt, etc. The pharmaceutically acceptable organic base addition salt includes, for example, primary amines such as methylamine, ethylamine, aniline, etc., secondary amines such as dimethylamine, diethylamine, pyrrolidine, piperidine, morphopline, piperazine, etc., tertiary amines such as trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, etc. and ammonia, etc.
The method for producing compounds (I) and (II) is given below.
Of Compound (I), Compound (I-1), Compound (I-2) or Compound (I-3) having the structures listed below is produced by culturing in a medium a microorganism belonging to the genus
Streptomyces
capable of producing Compound (I-1), Compound (I-2) or Compound (I-3) to form and accumulate Compound (I-1), Compound (I-2) or Compound (I-3) in the culture, and recovering Compound (I-1), Compound (I-2) or Compound (I-3) therefrom.
The specific preferred microorganism is an actinomyces such as
Streptomyces
sp. RE-701 which was isolated by the present inventors from the soil in the areas of Kitashitara-gun, Aichi; and
Streptomyces
sp. RE-629 which was isolated by the present inventors from the soil in the areas of Tsuno-gun, Yamaguchi.
The bacteriological properties of
Streptomyces
sp. RE-701 strain are described below.
I. Morphology
In a usual agar medium, the strain RE-701 possesses a septum and forms branched aerial mycelia and substrate mycelia. Characteristic fragmentation of

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