Tfpi inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2018072784-A1
Application number	US-201715681074-A
Country	US
Kind code	A1
Filing date	Aug 18, 2017
Priority date	Dec 19, 2008
Publication date	Mar 15, 2018
Grant date	—

Abstract

The invention provides peptides that bind Tissue Factor Pathway Inhibitor (TFPI), including TFPI-inhibitory peptides, and compositions thereof. The peptides may be used to inhibit a TFPI, enhance thrombin formation in a clotting factor-deficient subject, increase blood clot formation in a subject, and/or treat a blood coagulation disorder in a subject.

First claim

1 .- 55 . (canceled)

56 . A peptide that binds TFPI, comprising the following structure of formula (VIII):
X3001-X3002-X3003-X3004-X3005-X3006-X3007-X3008-X3009-X3010-X3011-X3012-X3013-X3014-X3015-X3016-X3017-X3018-X3019-X3020-X3021 (SEQ ID NO: 3120): wherein X3001 is either present or absent, whereby in case X3001 is present it is an amino acid selected from the group consisting of A, C, D, F, G, I, K, L, M, N, P, Q, R, S, T, W, E, H and Y; wherein X3002 is either present or absent, whereby in case X3002 is present it is an amino acid selected from the group consisting of A, C, D, F, H, K, M, N, P, R, S, T, W, Y, G, I and L; wherein X3003 is an amino acid selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, W and Y; wherein X3004 is an amino acid selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y and P; wherein X3005 is an amino acid selected from the group consisting of C, D, F, G, H, I, K, L, M, N, P, R, S, T, V, W and Y; wherein X3006 is an amino acid selected from the group consisting of A, W, C, K, P, R and H; wherein X3007 is an amino acid selected from the group consisting of Q, A, C, F, G, H, I, K, L, N, R, S, T, W and Y; wherein X3008 is an amino acid selected from the group consisting of A, C, F, G, H, K, L, M, N, P, Q, R, S, T, V, W, Y and I; wherein X3009 is an amino acid selected from the group consisting of A, C, F, G, H, I, L, M, R, S, T, V, W, Y and K; wherein X3010 is an amino acid selected from the group consisting of A, C, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; wherein X3011 is an amino acid selected from the group consisting of A, G, I, K, L, M, N, Q, R, S, T, V, W, Y, C, F and H; wherein X3012 is an amino acid selected from the group consisting of A, C, H, I, K, L and R; wherein X3013 is an amino acid selected from the group consisting of A, C, F, G, H, K, L, M, R, S, V, W, Y and I; wherein X3014 is an amino acid selected from the group consisting of A, C, F, G, H, I, L, M, N, Q, R, S, T, V, W, Y and K; wherein X3015 is an amino acid selected from the group consisting of A, K and R; wherein X3016 is an amino acid selected from the group consisting of A, F, K and R; wherein X3017 is an amino acid selected from the group consisting of A, C, F, G, I, K, L, N, Q, R, S, T, V, W, Y, H, A and M; wherein X3018 is an amino acid selected from the group consisting of A, C, F, I, K, L, M, Q, R, V, W and Y; wherein X3019 is an amino acid selected from the group consisting of A, C, D, E, F, G, H, K, L, N, P, Q, R, V, W, Y and I; wherein X3020 is an amino acid selected from the group consisting of A, C, F, G, H, K, L, M, N, Q, R, V, W, Y, I and P; and wherein X3021 is an amino acid selected from the group consisting of A, C, H, I, K, L, M, N, P, Q, R, T, V, W, Y, F and G.

57 . The peptide according to claim 56 ,
wherein X3001 is either present or absent, whereby in case X3001 is present it is an amino acid selected from the group consisting of A, C, D, G, I, K, L, M, N, P, Q, R, S, T, W, E, H and Y; wherein X3002 is either present or absent, whereby in case X3002 is present it is an amino selected from the group consisting of C, F, H, K, R, S, W, Y, G, I and L; wherein X3003 is an amino acid selected from the group consisting of A, C, D, F, G, H, I, K, L, M, N, P, Q, R, S, T and W; wherein X3004 is an amino acid selected from the group consisting of A, C, D, G, H, I, K, L, M, N, R, S, T, V and P; wherein X3005 is an amino acid selected from the group consisting of C, F, H, I, K, M, R, T, W and Y; wherein X3006 is an amino acid selected from the group consisting of P, H and A; wherein X3007 is an amino acid selected from the group consisting of C, G, R, W, A and L; wherein X3008 is an amino acid selected from the group consisting of A, C, F, G, H, K, L, M, N, Q, R, T, V, W, Y and I; wherein X3009 is an amino acid selected from the group consisting of C, I, R, V and K; wherein X3010 is an amino acid selected from the group consisting of A, C, G, H, I, K, L, M, Q, R, S and T; wherein X3011 is an amino acid selected from the group consisting of A, I, K, L, M, R, S, V, W, C, F and H; wherein X3012 is an amino acid selected from the group consisting of H and R; wherein X3013 is an amino acid selected from the group consisting of C, F, K, L, M, R, V and I; wherein X3014 is an amino acid selected from the group consisting of A, M, C, F, H, I, L, N, R, S, V, W and K; wherein X3015 is an amino acid selected from the group consisting of K and R; wherein X3016 is K; wherein X3017 is an amino acid selected from the group consisting of A, C, F, G, I, K, L, N, Q, R, S, T, V, W, H, A and M; wherein X3018 is an amino acid selected from the group consisting of A, K, C, I, L, R and W; wherein X3019 is an amino acid selected from the group consisting of A, C, E, H, K, N, Q, R and I; wherein X3020 is an amino acid selected from the group consisting of C, H, L, M, R, V, I and P; wherein X3021 is an amino acid selected from the group consisting of A, C, H, I, K, L, M, N, Q, R, V, W, Y, F and G.

58 . The peptide according to claim 56 ,
wherein X3001 is an amino acid selected from the group consisting of A, C, D, G, K, L, M, N, P, R, S, T, E, H and Y; wherein X3002 is an amino acid selected from the group consisting of C, K, R, W, Y, G, I and L; wherein X3003 is an amino acid selected from the group consisting of A, C, G, H, I, K, L, M, R, S, T and W; wherein X3004 is an amino acid selected from the group consisting of A, C, G, H, I, K, L, M, N, R, S, T and P; wherein X3005 is an amino acid selected from the group consisting of C, F, H, K, R and W; wherein X3006 is an amino acid selected from the group consisting of A, P and H; wherein X3007 is an amino acid selected from the group consisting of L, C, R and W; wherein X3008 is an amino acid selected from the group consisting of A, C, F, H, K, R, V, W, Y and I; wherein X3009 is an amino acid selected from the group consisting of C, R, V and K; wherein X3010 is an amino acid selected from the group consisting of A, C, K, L, Q, R and S; wherein X3011 is an amino acid selected from the group consisting of I, K, L, M, R, V, W, C, F and H; wherein X3012 is H; wherein X3013 is an amino acid selected from the group consisting of C, K, R, V and I; wherein X3014 is an amino acid selected from the group consisting of A, S, C, F, H, I, R and K; wherein X3015 is an amino acid selected from the group consisting of K and R; wherein X3016 is R; wherein X3017 is an amino acid selected from the group consisting of C, G, I, K, L, N, Q, R, S, T, V, H, A and M; wherein X3018 is an amino acid selected from the group consisting of K, C, I, R and W; wherein X3019 is an amino acid selected from the group consisting of C, E, H, K, R and I; wherein X3020 is an amino acid selected from the group consisting of C, M, I and P; wherein X3021 is an amino acid selected from the group consisting of A, C, H, I, K, L, M, N, Q, R, V, W, F and G.

59 . The peptide according to claim 56 , wherein the IC 50 of the peptide is less than 50,000 nM.

60 . The peptide according to claim 57 , wherein the IC 50 of the peptide is less than 10,000 nM.

61 . The peptide according to claim 58 , wherein the IC 50 of the peptide is less than 5,000 nM.

62 . The peptide according to claim 59 , wherein the IC 50 is determined by competition ELISA.

63 . A peptide that binds TFPI, comprising the following structure of formula (IX):
X3001-X3002-X3003-X3004-X3005-X3006-X3007-X3008-X3009-X3010-X3011-H—X3013-X3014-K/R—R—X3017-X3018-X3019-X3020-X3021 (IX) (SEQ ID NO: 3121) wherein X3001 and X3002 are independently either present or absent, wherein, if X3001 and/or X3002 are pres

Assignees

• Baxalta GmbH
• Baxalta Inc

Inventors

• Dockal Michael
• Ehrlich Hartmut
• Scheiflinger Friedrich
• Reimer Ulf
• Reineke Ulrich
• Polakowski Thomas
• Schneider Eberhard

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K7/08 Primary

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K14/4703 Primary

  Inhibitors; Suppressors · CPC title