US 6,642,355 B2 · Endothelin-antagonizing peptide

Abstract

The invention relates to an endothelin antagonistic peptide of the formula (I): X-A-Trp-B-Gly-Thr-E-G-Y (I) SEQ ID NO: 2 wherein represents Asn or Asp; B represents His or Lys; E represents Ala or Ser; G represents Ala or Pro; X represents X1-Gly or and Y represents hydroxy, lower alkoxy, amino, wherein X1, X3, Y1, Y2 and Z are further defined, or a pharmaceutically acceptable salt thereof.

A peptide 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 X1-Gly or
Y represents hydroxy, lower alkoxy, amino, or
wherein
each of X1 and X3 represents hydrogen, benzyloxy-carbonyl, t-butyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, or carbonyl-substituted or unsubstituted lower alkanoyl;
each of X2 and Y2 represents hydrogen;
Y1 represents hydroxy, lower alkoxy or amino;
or
X1 and Y1, or X2 and Y2 are combined together to form a single bond as X1—Y1 or X2—Y2;
and
Z represents hydroxy, lower alkoxy, benzyloxy, benzhydryloxy, amino,
where
Z2 is hydroxy, lower alkoxy, benzyloxy, benzhydryloxy or amino,
Gly-Z1
where
Z1 is hydroxy, lower alkoxy, benzyloxy, benzhydryloxy, amino,
where Z2 is as defined previously, or Z1 is combined with X1 to form a single bond as X1-Z1,
Ala-Z1
where Z1 is as defined previously,
Val-Z1
where Z1 is as defined previously,
Trp-Z1
where Z1 is as defined previously,
Trp-Gly-Z1
where Z1 is as defined previously,
Trp-Asn-Tyr-Tyr-Trp-Z1 SEQ ID NO:
3
where Z1 is as defined previously,
Trp-Phe-Phe-Asn-Tyr-Tyr-7Hyt-Z1 SEQ ID NO:
4
where Z1 is as defined previously, and 7Hyt represents 7-hydroxytryptophan,
Trp-Ile-Ile-Trp-Z1 SEQ ID NO:
5
where Z1 is as defined previously,
Trp-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
6
where Z1 is as defined previously, and W represents Ala, Ser or Cys,
Trp-W-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
7
where Z1 and W are as defined previously,
Trp-Val-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
8
wherein Z1 and W are as defined previously,
Trp-Leu-Tyr-Phe-W-His-Gln-Asp-Val-Ile-Trp-Z1 SEQ ID NO:
9
wherein Z1 and W are as defined previously,
Trp-Val-Tyr-Phe-W-Phe-Phe-Asn-Tyr-Tyr-Trp-Z1 SEQ ID NO:
10
wherein Z1 and W are as defined previously,
Trp-Phe-Phe-Asn-Tyr-Tyr-W-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
11
wherein Z1 and W are as defined previously,
Trp-Phe-Phe-Asn-Tyr-Tyr-Asn-Ile-Ile-Trp-Z1 SEQ ID NO:
12
wherein Z1 is as defined previously,
J-Phe-M-Q-Tyr-R-T-Z1 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
Trp-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 covalent bond simultaneously, and Z1 is as defined previously, provided that
(1) when G represents Pro;
X represents X1-Gly;
Y represents
wherein X1 and Y1 are combined together to form a single bond as X1-Y1;
then Z is not a group selected from the group consisting of
(a) Trp-Phe-Phe-Asn-Tyr-Tyr-7Hyt-Z1 SEQ ID NO:
4
where Z1 is as defined previously, and 7Hyt represents 7-hydroxytryptophan,
(b) Trp-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
6
where Z1 is as defined previously,
(c) Trp-Ala-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
7
where Z1 is as defined previously,
(d) Trp-Val-Tyr-Tyr-Ala-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
8
where Z1 is as defined previously,
(e) Trp-Leu-Tyr-Phe-W-His-Gln-Asp-Val-Ile-Trp-Z1 SEQ ID NO:
9
where Z1 and W are as defined previously,
(f) Trp-Phe-Phe-Asn-Tyr-Tyr-T1-Z1 SEQ ID NO:
13
where Z1 is as defined previously;
T1 is Trp, Ala, Phe, Tyr, Trp-Trp,
Asn-Tyr-Tyr-Trp, SEQ ID NO:
14
Trp-Asn-Tyr-Tyr-Trp, SEQ ID NO:
15
or
Trp-Val-Tyr-Phe-W-His-Leu-Asp-Ile-Ile-Trp, SEQ ID NO:
16
where W is as defined previously, and
(g) Trp-Phe-Phe-Asn-Tyr-Tyr-T-Z3 SEQ ID NO:
13
where T is as defined previously;
Z3 is hydroxy,
where Z2 is as defined previously;
(2) when G represents Pro;
X represents X1-Gly;
Y represents
X1 represents hydrogen and Y1 represents hydroxy;
then Z is not a group selected from the group consisting of
(h) Trp-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
6
where Z1 is as defined previously,
(i) Trp-Val-Tyr-Tyr-Ala-His-Leu-Asp-Ile-Ile-Trp-Z1 SEQ ID NO:
8
(j) Trp-Leu-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp-Z1 SEQ ID NO:
9
where Z1 is as defined previously,
or a pharmaceutically acceptable salt thereof.

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Endothelin-antagonizing peptide

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Endothelin-antagonizing peptide

Life of this patent

Abstract

Claims2