Octapeptide bombesin analogs

Details Octapeptide bombesin analogs Octapeptide bombesin analogs

1999-03-02

2001-10-23

Davenport, Avis M. (Department: 1654)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

8 to 10 amino acid residues in defined sequence

C530S300000, C530S323000, C514S012200, C514S015800

Reexamination Certificate

active

06307017

ABSTRACT:

SUMMARY OF THE INVENTION
In general, the invention features a linear (i.e., non-cyclic) analog of biologically active mammalian gastrin-releasing peptide (GRP), amphibian bombesin, or mammalian growth hormone releasing factor (GRF) having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell; cleavage of a peptide bond in the active site of naturally occurring bombesin, GRP, or GRF is unnecessary for in vivo biological activity. The analog has one of the following modifications: (a) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, (b) a replacement of two amino acid residues within the active site with a synthetic amino acid, e.g., statine, AHPPA, or ACHPA, a &bgr;-amino acid, or a &ggr;-amino acid residue, or (c) a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue.
In preferred embodiments the analog is capable of acting as a competitive inhibitor of the naturally occurring peptide by binding to the receptor and, by virtue of one of the modifications, failing to exhibit the in vivo biological activity of the naturally occurring peptide.
The locations of the modifications that give rise to antagonists are determined by the location of the active site in the naturally occuring peptide. For example, the linear peptides for which introduction of a non-peptide bond between the carboxyl terminal and adjacent amino acid residues, or the replacement of the natural carboxyl terminal and adjacent amino acid residues with a synthetic, &bgr;-, or &ggr;-amino acid residue, or the deletion (“des”) of the C-terminal amino acid residue are useful in creating or enhancing antagonist activity are those in which activity is associated with the two C-terminal amino acid residues of the amino acid chain. Similarly, where the active site is located in the amino terminal portion of the naturally occuring peptide, the corresponding analogs of the invention will possess modifications in their amino terminal portions.
In preferred embodiments the active site includes at least one amino acid residue located in the carboxyl terminal half of the naturally occurring biologically active peptide and that amino acid residue is located in the carboxyl terminal half of the linear peptide.
In preferred embodiments the binding sites includes at least one amino acid residue located in the amino terminal half of the naturally occurring biologically active peptide and that amino acid residue is located in the amino terminal half of the linear peptide.
Modifications can be introduced in a region involved in receptor binding, or in a non-binding region. Preferably, analogs of the invention are 25% homologous, most preferably, 50% homologous, with the naturally occurring peptides.
The analogs of the invention may have one of the modifications given in the generic formula given below either a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue; or a synthetic amino acid, e.g. a statine, an AHPPA, or an ACHPA, a &bgr;-amino acid, or a &ggr;-amino acid residue in place of two natural amino acid residues; or a deletion of the C-terminal amino acid residue, accompanied by the addition of a substituent on the actual C-terminal group and the presence of an N-terminal residue that is not the natural N-terminal amino acid residue of the peptides from which the analogs are derived. (Statine, AHPPA, and ACHPA have the chemical structures defined above. Where statine is used herein, AHPPA or ACHPA may also be used.)
By non-peptide bond is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH
2
—NH; or, less preferably that CO—NH is replaced with any of CH
2
—S, CH
2
—O, CH
2
—CH
2
, CH
2
—CO, or CO—CH
2
. (A detailed discussion of the chemistry of non-peptide bonds is given in Coy et al. (1988) Tetrahedron 44,3:835-841, hereby incorporated by reference, Tourwe (1985) Janssen Chim. Acta 3:3-15, 17-18, hereby incorporated by reference, and Spatola (1983) in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, (B. Weinstein, ed.) M. Dekker, New York and Basel, pp. 267-357, hereby incorporated by reference.)
One modification of the naturally occurring peptide to create an antagonist is of the amino terminal end of the molecule, such as those described for the amino terminal positions in the generic formula below; for example, the N-terminal amino acid residue, which is A
0
or, if A
0
is deleted, is A
1
or, if A
0
and A
1
are deleted, is A
2
below, may be an aromatic D-isomer, or may be an alkylated amino acid residue. (Where “D” is not designated as the configuration of an amino acid, L is intended.)
The therapeutic peptide includes between seven and ten amino acid residues, inclusive, and is an analog of one of the following peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) the ten amino acid carboxy-terminal region of mammalian GRP; and (c) the ten amino acid carboxy-terminal region of amphibian bombesin. The therapeutic peptide is of the following formula:
wherein
A
0
=pGlu, Gly, Nle, &agr;-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br. NO
2
, OH, H or CH
3
), Trp, Cys, or &bgr;-Nal, or is deleted;
A
1
=the D or L-isomer of any of pGlu, Nle, (&agr;-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO
2
, OH, H or CH
3
), F
5
-Phe, Trp, Cys, or &bgr;-Nal, or is deleted;
A
2
=pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO
2
, OH, H or CH
3
), Trp, Cys, &bgr;-Nal, His, 1-methyl-His, or 3-methyl-His;
A
4
=Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, &agr;-ainobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO
2
, OH, H or CH
3
), Trp, Cys, or &bgr;-Nal;
A
5
=Gln, Asn, Gly, Ala, Leu, Ile, Nle, &agr;-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH
3
), Trp, Thr, or &bgr;-Nal;
A
6
=Sar, Gly, or the D-isomer of any of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO
2
, OH, H or CH
3
), Trp, Cys, or B-Nal;
A
7
=i-methyl-His, 3-methyl-His, or His; provided that, if A
0
is present, Al cannot be pGlu; further provided that, if A
0
or Al is present, A
2
cannot be pGlu; further provided that, when A
0
is deleted and A
1
is pGlu, R
1
must be H and R
2
must be the portion of Glu that forms the imine ring in pGlu; and further provided that, W can be any one of the following:
wherein R
3
is CHR
20
—(CH
2
)
n1
(where R
20
is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z
1
is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, Gln, p-X-Phe (where X=H, F, Cl, Br, NO
2
, OH, or CH3), F
5
-Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or &bgr;-nal; and V is either to OR
4
, or
where R
4
is any of C
1-20
alkyl, C
3-20
alkenyl, C
3-20
alkinyl, phenyl, naphthyl, or C
7-10
phenylalkyl, and each R
5
, and R
6
, independently, is any of H, C
1-12
alkyl, C
7-10
phenylalkyl, lower acyl, or,
where R
22
is any of H, C
1-12
alkyl, C
7-10
phenylalkyl, or lower acyl; provided that, when one of R
5
or R
6
is —NHR
22
, the other is H;
wherein R
4
is CH
2
—NH, CH
2
—S, CH
2
—O, CO—CH
2
, CH
2
—CO, or CH
2
—CH
2
, and each Z
1
and Z
2
, independently, is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, Gln, &bgr;-Nal, p-X-Phe (where X=H, F, Cl, Br, NO
2
, OH or CH
3
), F
5
-Phe, Trp, Cys, Met, Pro, HyPro, or cylcohexyl-Ala; and V is either OR
5
or
where each R
3
, R
5
, R
6
, and R
7
, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl;
wherein Z
1
is the identifying group of any one of

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