Patent EA-001220-B1 (EA)
Title: Peptides or peptidemimetics bound to thrombopoietin receptor, pharmaceutical composition and method of treatment
Inventor: DOWER WILLIAM J
IPC: C07K/
Filed: 1996-06-07
Abstract: 1. A pertide or peptidemimetics that binds to thrombopoietin receptor and activates it, said compound having a molecular weight of less than about 8000 daltons, a binding affinity to thrombopoietin receptor as expressed by an IC50 of no more than about 100 μm and comprises a sequence of amino acids: X1 X2 X3 X4 X5 X6 X7 where X1 is C, L, M, P, Q, V; X2 is F, K, L, N, Q, R, S, T or V; X3 is C, F, I, L, M, R, S, V or W; X4 is any of the 20 genetically coded L-amino acids; X5 is A, D, E, G, K, M, Q, R, S, T, V or Y; X6 is C, F, G, L, M, S, V, W or Y; and X7 is C, G, I, K, L, M, N, R or V. 2. The pertide or peptidemimetics of claim 1, wherein said sequence of amino acids is cyclized. 3. The pertide or peptidemimetics of claim 1, wherein said sequence of amino acids is dimerized. 4. The pertide or peptidemimetics of claim 1, wherein said compound comprises the sequence of amino acids  C X2 X3 X4 X5 X6 X7 where X2 is K, L, N, Q, R, S, T or V; X3 is C, F, I, L, M, R, S or V; X4 is any of the 20 genetically coded L-amino acids; X5 is A, D, E, G, S, V or Y; X6 is C, F, G, L, M, S, V, W or Y; and X7 is C, G, I, K, L, M, N, R or V. 5. The pertide or peptidemimetics of claim 3, wherein X4 is A, E, G, H, K, L, M, P, Q, R, S, T, or W. 6. The pertide or peptidemimetics of claim 5, wherein X2 is S or T; X3 is L or R; X4 is R; X5 is D, E, or G; X6 is F, L, or W; and X7 is I, K, L, R, or V. 7. The pertide or peptidemimetics of claim 4, wherein said compound comprises a sequence of amino acids: X8 C X2 X3 X4 X5 X6 X7 where X2 is F, K, L, N, Q, R, S, T or V; X3 is C, F, I, L, M, R, S, V or W; X4 is any of the 20 genetically coded L-amino acids; X5 is A, D, E, G, K, M, Q, R, S, T, V or Y; X6 is C, F, G, L, M, S, V, W or Y; X7 is C, G, I, K, L, M, N, R or V; and X8 is any of the 20 genetically coded L-amino acids. 8. The pertide or peptidemimetics of claim 7, wherein X8 is G, S, Y or R. 9. The pertide or peptidemimetics d of claim 7, wherein said compound comprises a sequence of amino acids: G G C T L R E W L H G G F C G G. 10. The pertide or peptidemimetics of claim 1, wherein said compound comprises a sequence of amino acids:  X8 G X1 X2 X3 X4 X5 W X7 where X1 is L, M, P, Q, or V; X2 is F, R, S, or T; X3 is F, L, V, or W; X4 is A, K, L, M, R, S, V, or T; X5 is A, E, G, K, M, Q, R, S, or T; X7 is C, I, K, L, M or V; and X8 is any of the 20 genetically coded L-amino acids. 11. The pertide or peptidemimetics of claim 10, wherein X1 is P; X2 is T; X3 is L; X4 is R; X5 is E or Q; X7 is I or L.  12. The pertide or peptidemimetics of claim 11, wherein comprises a sequence of amino acids:  X9 X8 G X1 X2 X3 X4 X5 W X7 where X8 is A, C, D, E, K, L, Q, R, S, T, or V; and X9 is A, C, E, G, I, L, M, P, R, Q, S, T, or V.  13. The pertide or peptidemimetics of claim 12, wherein X8 is D, E, or K; and X9 is A or I.  14. The pertide or peptidemimetics of claim 13, wherein comprises a sequence of amino acids: G G C A D G P T L R E W I S F C G G; or G N A D G P T L R Q W L E G R R P K N; or G G C A D G P T L R E W I S F C G G K; or T I K G P T L R Q W L K S R E H T S; or S I E G P T L R E W L T S R T P H S; or L A I E G P T L R Q W L H G N G R D T; or C A D G P T L R E W I S F C; or I E G P T L R Q W L A A R A. 15. The pertide or peptidemimetics that binds to thrombopoietin receptor and activates it, comprising the following structure:     16. The pertide or peptidemimetics that binds to thrombopoietin receptor and activates it, comprising the following structure:   17. A pharmaceutical composition comprising the pertide or peptidemimetics of any preceding claim 1 to 16 and a pharmaceutically acceptable carrier. 18. 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 the pertide or peptidemimetics of any preceding claim 1 to 16. 19. The method of claim 18, 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.