Claims
- 1. A compound that binds to thrombopoietin receptor, said compound having:
- (1) a molecular weight of less than about 8000 daltons, and
- (2) a binding affinity to thrombopoietin receptor as expressed by an IC.sub.50 of no more than about 100 .mu.m.
- 2. The compound of claim 1, wherein said compound is a peptide, and,
- wherein from zero to all of the --C(O)NH-- linkages of the peptide have been replaced by a linkage selected from the group consisting of a --CH.sub.2 OC(O)NR-- linkage; a phosphonate linkage; a --CH.sub.2 S(O).sub.2 NR-- linkage; a --CH.sub.2 NR-- linkage; a --C(O)NR.sup.6 -- linkage; and a --NHC(O)NH-- linkage; and wherein R is hydrogen or lower alkyl and R.sup.6 is lower alkyl,
- further wherein the N-terminus of said peptide is selected from the group consisting of a --NRR.sup.1 group; a --NRC(O)R group; a --NRC(O)OR group; a --NRS(O).sub.2 R group; a --NHC(O)NHR group; a succinimide group; a benzyloxycarbonyl-NH-- group; and a benzyloxycarbonyl-NH-- group having from 1 to 3 substituents on the phenyl ring selected from the group consisting of lower alkyl, lower alkoxy, chloro, and bromo; and wherein R and R.sup.1 are independently selected from the group consisting of hydrogen and lower alkyl,
- and still further wherein the C-terminus of said peptide has the formula --C(O)R.sup.2 where R.sup.2 is selected from the group consisting of hydroxy, lower alkoxy, and --NR.sup.3 R.sup.4 where R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl and where the nitrogen atom of the --NR.sup.3 R.sup.4 group can optionally be the amine group of the N-terminus of the peptide so as to form a cyclic peptide,
- and physiologically acceptable salts thereof.
- 3. A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
- 4. A method for treating a patient suffering from a disorder that is susceptible to treatment with a thrombopoietin agonist, comprising admistering to the patient, a therapeutically effective dose or amount of a compound of claim 1.
- 5. The method of claim 4, wherein the compound administered to the patient is a peptide, and,
- wherein from zero to all of the --C(O)NH-- linkages of the peptide have been replaced by a linkage selected from the group consisting of a --CH.sub.2 OC(O)NR-- linkage; a phosphonate linkage; a --CH.sub.2 S(O).sub.2 NR-- linkage; a --CH.sub.2 NR-- linkage; a --C(O)NR.sup.6 -- linkage; and a --NHC(O)NH-- linkage; and wherein R is hydrogen or lower alkyl and R.sup.6 is lower alkyl,
- further wherein the N-terminus of said peptide is selected from the group consisting of a --NRR.sup.1 group; a --NRC(O)R group; a --NRC(O)OR group; a --NRS(O).sub.2 R group; a --NHC(O)NHR group; a succinimide group; a benzyloxycarbonyl-NH-- group; and a benzyloxycarbonyl-NH-- group having from 1 to 3 substituents on the phenyl ring selected from the group consisting of lower alkyl, lower alkoxy, chloro, and bromo; and wherein R and R.sup.1 are independently selected from the group consisting of hydrogen and lower alkyl, and still further wherein the C-terminus of said peptide has the formula --C(O)R.sup.2 where R.sup.2 is selected from the group consisting of hydroxy, lower alkoxy, and --NR.sup.3 R.sup.4 where R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl and where the nitrogen atom of the --NR.sup.3 R.sup.4 group can optionally be the amine group of the N-terminus of the peptide so as to form a cyclic peptide,
- and physiologically acceptable salts thereof.
- 6. The compound of claim 2, wherein said compound comprises a sequence of amino acids (SEQ ID NO:2):
- X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7
- where X.sub.1 is C, L, M, P, Q, V; X.sub.2 is F, K, L, N, Q, R, S, T or V; X.sub.3 is C, F, I, L, M, R, S, V or W; X.sub.4 is any of the 20 genetically coded L-amino acids; X.sub.5 is A, D, E, G, K, M, Q, R, S, T, V or Y; X.sub.6 is C, F, G, L, M, S, V, W or Y; and X.sub.7 is C, G, I, K, L, M, N, R or V.
- 7. The compound of claim 6, wherein said sequence of amino acids is cyclized.
- 8. The compound of claim 6, wherein said sequence of amino acids is dimerized.
- 9. The compound of claim 6, wherein the compound comprises the sequence of amino acids (SEQ ID NO:14)
- C X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7
- where X.sub.2 is K, L, N, Q, R, S, T or V; X.sub.3 is C, F, I, L, M, R, S or V; X.sub.4 is any of the 20 genetically coded L-amino acids; X.sub.5 is A, D, E, G, S, V or Y; X.sub.6 is C, F, G, L, M, S, V, W or Y; and X.sub.7 is C, G, I, K, L, M, N, R or V.
- 10. The compound of claim 8, wherein X.sub.4 is A, E, G, H, K, L, M, P, Q, R, S, T, or W.
- 11. The compound of claim 10, wherein X.sub.2 is S or T; X.sub.3 is L or R; X.sub.4 is R; X.sub.5 is D, E, or G; X.sub.6 is F, L, or W; and X.sub.7 is I, K, L, R, or V.
- 12. The compound of claim 9, wherein said compound comprises a sequence of amino acids (SEQ ID NO:16):
- X.sub.8 C X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7
- where X.sub.2 is F, K, L, N, Q, R, S, T or V; X.sub.3 is C, F, I, L, M, R, S, V or W; X.sub.4 is any of the 20 genetically coded L-amino acids; X.sub.5 is A, D, E, G, K, M, Q, R, S, T, V or Y; X.sub.6 is C, F, G, L, M, S, V, W or Y; X.sub.7 is C, G, I, K, L, M, N, R or V; and X.sub.8 is any of the 20 genetically coded L-amino acids.
- 13. The compound of claim 12, wherein X.sub.8 is G, S, Y or R.
- 14. The compound of claim 12, wherein said compound comprises a sequence of amino acids (SEQ ID NO:15): G G C T L R E W L H G G F C G G.
- 15. The compound of claim 6, wherein said compound comprises a sequence of amino acids (SEQ ID NO:3):
- X.sub.8 G X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 W X.sub.7
- where X.sub.1 is L, M, P, Q, or V; X.sub.2 is F, R, S, or T; X.sub.3 is F, L, V, or W; X.sub.4 is A, K, L, M, R, S, V, or T; X.sub.5 is A, E, G, K, M, Q, R, S, or T; X.sub.7 is C, I, K, L, M or V; and X.sub.8 is any of the 20 genetically coded L-amino acids.
- 16. The compound of claim 15, wherein X.sub.1 is P; X.sub.2 is T; X.sub.3 is L; X.sub.4 is R; X.sub.5 is E or Q; X.sub.7 is I or L (SEQ ID NO:4).
- 17. The compound of claim 16, wherein said compound comprises a sequence of amino acids (SEQ ID NO:5):
- X.sub.9 X.sub.8 G X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 W X.sub.7
- where X.sub.8 is A, C, D, E, K, L, Q, R, S, T, or V; and X.sub.9 is A, C, E, G, I, L, M, P, R, Q, S, T, or V.
- 18. The compound of claim 17, wherein X.sub.8 is D, E, or K; and X.sub.9 is A or I.
- 19. The compound of claim 18, wherein said compound is selected from the group consisting of (SEQ ID NOS: 6-13, respectively) G G C A D G P T L R E W I S F C G G; G N A D G P T L R Q W L E G R R P K N; G G C A D G P T L R E W I S F C G G K; T I K G P T L R Q W L K S R E H T S; S I E G P T L R E W L T S R T P H S; L A I E G P T L R Q W L H G N G R D T; C A D G P T L R E W I S F C; and I E G P T L R Q W L A A R A.
- 20. The method of claim 4, wherein said compound that is administered to the patient comprises a sequence of amino acids (SEQ ID NO:15):
- C X.sub.2 X.sub.3 X.sub.4 X.sub.5 X.sub.6 X.sub.7
- where X.sub.2 is K, L, N, Q, R, S, T or V; X.sub.3 is C, F, I, L, M, R, S or V; X.sub.4 is any of the 20 genetically coded L-amino acids; X.sub.5 is A, D, E, G, S, V or Y; X.sub.6 is C, F, G, L, M, S, V, W or Y; and X.sub.7 is C, G, I, K, L, M, N, R or V.
- 21. The method of claim 20, wherein X.sub.4 is A, E, G, H, K, L, M, P, Q, R, S, T or W.
- 22. The method of claim 21, wherein X.sub.2 is S or T; X.sub.3 is L or R; X.sub.4 is R; X.sub.5 is D, E, or G; X.sub.6 is F, L, or W; and X.sub.7 is I, K, L, R, or V.
- 23. The method of claim 22, wherein said compound that is administered to the patient comprises a sequence of amino acids (SEQ ID NO:15): G G C T L R E W L H G G F C G G.
- 24. The method of claim 4, wherein the disorder susceptible to treatment with a thrombopoietin agonist is selected from the group consisting of:
- hematological disorders and thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions.
- 25. The method of claim 4, wherein said compound that is administered to the patient comprises a sequence of amino acids (SEQ ID NO:16):
- X.sub.8 G X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 W X.sub.7
- where X.sub.1 is L, M, P, Q, or V; X.sub.2 is F, R, S, or T; X.sub.3 is F, L, V, or W; X.sub.4 is A, K, L, M, R, S, V, or T; X.sub.5 is A, E, G, K, M, Q, R, S, or T; X.sub.7 is C, I, K, L, M or V; and X.sub.8 residue is any of the 20 genetically coded L-amino acids.
- 26. The method of claim 25, wherein X.sub.1 is P; X.sub.2 is T; X.sub.3 is L; X.sub.4 is R; X.sub.5 is E or Q; X.sub.7 is I or L.
- 27. The method of claim 26, wherein said compound comprises a sequence of amino acids (SEQ ID NO:5):
- X.sub.9 X.sub.8 G X.sub.1 X.sub.2 X.sub.3 X.sub.4 X.sub.5 W X.sub.7
- where X.sub.8 is A, C, D, E, K, L, Q, R, S, T, or V; and X.sub.9 is A, C, E, G, I, L, M, P, R, Q, S, T, or V.
- 28. The method of claim 27, wherein X.sub.8 is D, E, or K; and X.sub.9 is A or I.
- 29. The method of claim 28, wherein the compound that is administered to the patient is selected from the group consisting of (SEQ ID NOS: 6-13, respectively) G G C A D G P T L R E W I S F C G G; G N A D G P T L R Q W L E G R R P K N; G G C A D G P T L R E W I S F C G G K; T I K G P T L R Q W L K S R E H T S; S I E G P T L R E W L T S R T P H S; L A I E G P T L R Q W L H G N G R D T; C A D G P T L R E W I S F C; and I E G P T L R Q W L A A R A.
- 30. A compound that binds to thrombopoietin receptor, wherein said compound is selected from the group consisting of ##STR102##
- 31. A method for treating a patient suffering from a disorder that is susceptible to treatment with a thrombopoietin agonist, comprising administering to the patient a compound selected from the group consisting of
Parent Case Info
This application is filed pursuant to 35 U.S.C. .sctn.371 as a United States National Phase Application of International Application No. PCT/GB96/09623 filed Jun. 7, 1996 which claims priority from U.S. Ser. No. 08/485,301 filed Jun. 7, 1995 and now abandoned and U.S. Ser. No. 08/478,128 filed Jun. 7, 1995 and now abandoned.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US96/09623 |
6/7/1996 |
|
|
12/4/1997 |
12/4/1997 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO96/40750 |
12/19/1996 |
|
|
US Referenced Citations (4)
Number |
Name |
Date |
Kind |
5141851 |
Brown et al. |
Aug 1992 |
|
5358934 |
Borovsky et al. |
Oct 1994 |
|
5411942 |
Widmer et al. |
May 1995 |
|
5932546 |
Barrett et al. |
Aug 1999 |
|
Foreign Referenced Citations (1)
Number |
Date |
Country |
WO 9617062 A1 |
Jun 1996 |
WOX |
Non-Patent Literature Citations (2)
Entry |
Kato, et al. Purification and Characterization of Thrombopoietin, J. Biochem. 1995, vol. 118, pp. 229-236. |
Wada, et al. Characterization of the Truncated Thrombopoietin Variants. Biochemical and Biophysical Research Communications, Aug. 24, 1995, vol. 213, No. 3, pp. 1091-1098. |
Continuation in Parts (2)
|
Number |
Date |
Country |
Parent |
485301 |
Jun 1995 |
|
Parent |
478128 |
Jun 1995 |
|