Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-07-20
2004-04-06
Sisson, Bradley L. (Department: 1634)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C530S350000, C530S324000
Reexamination Certificate
active
06716811
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to novel compounds that have affinity for the granulocyte-colony stimulating factor receptor (G-CSFR). More particularly, the invention relates to such compounds which act as G-CSF mimetics by activating or inactivating the G-CSFR, or by affecting ligand binding to G-CSFR. The invention additionally relates to methods of using the novel compounds and pharmaceutical compositions containing a compound of the invention as the active agent. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides G-CSF mimetics for use in the treatment of human disease.
BACKGROUND
Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that specifically stimulates proliferation and differentiation of cells of the neutrophilic lineage.
G-CSF is a cytokine that binds to and activates the granulocyte-colony stimulating factor receptor (G-CSFR). G-CSFR is expressed on the surface of mature neutrophils and cells committed to the neutrophilic lineage, with receptor density varying from 190 to more than 1400 sites per cell. The receptor is a member of the cytokine receptor superfamily; it contains a cytokine receptor-homologous domain responsible for G-CSF binding, an immunoglobulin-like domain, three fibronectin type III domains, a transmembrane region, and an intracellular domain. The observed affinity of G-CSF for its receptor is about 100 pM.
The complete G-CSF protein has become an important therapeutic agent in clinical indications involving depressed neutrophil counts. Such indications include chemotherapy-induced neutropenia, AIDS and community acquired pneumonia. Furthermore, G-CSF antagonists may be useful in the treatment of some diseases caused by an inappropriate or undesirable activation of G-CSFR.
There remains a need, however, for compounds that bind specifically to G-CSFR, both for studies of the important biological activities mediated by the receptor and for treatment of diseases, disorders and conditions that would benefit from activating or inactivating G-CSFR. The present invention provides such compounds, and also provides pharmaceutical compositions and methods for using the compounds as therapeutic agents.
SUMMARY OF THE INVENTION
In one embodiment, the invention provides compounds comprising a peptide chain that binds to G-CSFR. In one aspect, the peptide chain is approximately 10 to 40 amino acids in length and contains a sequence of amino acids of formula (I)
CX
1
X
2
X
3
X
4
X
5
X
6
X
7
X
8
C (SEQ ID NO: 1) (I)
wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X
1
is A, N, S, F, D, G, L, T, E, V, P, Q, H, M or K; X
2
is M, G, R, H, D, I, V, A, S, E, N, F, Y, P, C, W or T; X
3
is E, V, W, F, M, A, N, S, L, T, Y, G or P; X
4
is V, I, G, Q, W, M, T, Y, L, P, D, C, E or A; X
5
is M, E, W, L, P, N, I, T, V, F, Y, Q, S, R, W, G, H or D; X
6
is H, A, W, Y, V, F, Q, M, N, E, S, D, P or G; X
7
is M, F, Y, V, N, L, H, D, S, W, G, Q, C or T; and X
8
is C, Y, R, I, K, W, L, E, M, H, A, T, F, D, P, G or Q.
In another aspect, the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (II)
X
I
1
X
I
2
X
I
3
SGWVWX
I
4
(SEQ ID NO: 2) (II)
wherein each amino acid is indicated by the standard one-letter abbreviation, and wherein X
I
1
is S, Q, R, L or Y; X
I
2
is N, S, T, A or D; X
I
3
is E, D or N; and X
I
4
is L V, T, P or H.
In another aspect, the peptide chain is 6 to 40 amino acids in length and contains a sequence of amino acids of formula (III)
ERX
II
1
X
II
2
X
II
3
C (SEQ ID NO: 3) (III)
wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X
II
1
is D, L, S, G, E, A, K or Y; X
II
2
is W, Y, F, L or V; and X
II
3
is F, G, M or L.
In still another aspect, the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (IV)
X
III
1
MVYX
III
2
X
III
3
PX
III
4
W (SEQ ID NO: 4) (IV)
wherein each amino acid in indicated by standard one-letter abbreviation, and wherein X
II
1
is D or E; X
III
2
is A or T; X
III
3
is Y or V; and X
III
4
is P or Y.
In an additional aspect, the invention provides compounds comprising a peptide chain approximately 12 to 40 amino acids in length and contains a sequence of amino acids of formula (V)
CX
IV
1
X
IV
2
X
IV
3
X
IV
4
X
IV
5
X
IV
6
X
IV
7
X
IV
8
X
IV
9
X
IV
10
C (SEQ ID NO: 5) (V)
wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X
IV
1
is E, G, P, N, R, T, W, S, L, H, A, Q or Y; X
IV
2
is S, T, E, A, D, G, W, P, L, N, V, Y, R or M; X
IV
3
is R, Y, V, Q, E, T, L, P, S, K, M, A or W; X
IV
4
is L, M, G, F, W, R, S, V, P, A, D, C or T; X
IV
5
is V, T, A, R, S, L, W, C, I, E, P, H, F, D or Q; X
IV
6
is E, Y, G, T, Q, M, S, N, A or P; X
IV
7
is C, V, D, G, L, W, E, V, I, S, M or A; X
IV
8
is S, Y, A, W, P, V, L, Q, G, K, F, I, E or D; X
IV
9
is R, W, M, D, H, V, G, A, Q, L, S, E or Y; X
IV
10
is M, L, I, S, V, P, W, F, T, Y, R, or Q.
In another aspect the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (VI)
X
V
1
X
V
2
X
V
3
X
V
4
X
V
5
X
V
6
CX
V
7
X
V
8
(SEQ ID NO: 6) (VI)
wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X
V
1
is E, C, Q, V, or Y; X
V
2
is E, A, L, M, S, W, or Q; X
V
3
is K, R or T; X
V
4
is L, A, or V; X
V
5
is R, A, M, H, E, V, L, G, D, Q, or S; X
V
6
is E or V; X
V
7
is A or G; X
V
8
is R H, G or L.
In a further aspect, the peptide chain is approximately 10 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (VII)
X
VI
1
X
VI
2
X
VI
3
X
VI
4
X
VI
5
EX
VI
6
X
VI
7
X
VI
8
X
VI
9
(SEQ ID NO: 7) (VII)
wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X
VI
5
is A, E or G; X
VI
2
is E, H or D; X
VI
3
is R or G; X
VI
4
is K, Y, M, N, Q, R, D, I, S or E; X
VI
5
is A, S or P; X
VI
6
is E, D, T, Q, K or A: X
VI
7
is R, W, K, L, S, A or Q; X
VI
8
is R or E; and X
VI
9
is W, G, or R.
In a final aspect, the invention also provides peptides that, while not necessarily corresponding to one of the above-defined formulas, bind to G-CSFR.
In some contexts, the compounds of the invention are preferably in the form of a dimer. It is also preferred, in some contexts, that the compounds of the invention include a peptide wherein the N-terminus of the peptide is coupled to a polyethylene glycol molecule. In some contexts, it is preferred that the compounds of the invention include a peptide wherein the N-terminus of the peptide is acetylated. In addition, it is preferred, in some contexts, that the compounds of the invention include a peptide wherein the C-terminus of the peptide is amidated.
The invention also provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, as well as a method for treating a patient who would benefit from a G-CSFR modulator, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.
REFERENCES:
patent: 5298603 (1994-03-01), Habermann et al.
patent: 5358707 (1994-10-01), Reichert et al.
patent: 5589456 (1996-12-01), Smith et al.
patent: 5651963 (1997-07-01), Halenbeck et al.
patent: 5773581 (1998-06-01), Camble et al.
patent: 5824778 (1998-10-01), Ishikawa et al.
patent: 6100070 (2000-08-01), Zurfluh et al.
patent: 0494260 (1992-07-01), None
Balu Palani
Cwirla Steven E.
Duffin David J.
McEowen Merrill Barbara
Piplani Sunila
Affymax, Inc.
Biotechnology Law Group
Kreusser, Esq. Edward O.
Sisson Bradley L.
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