Compstatin analogs and their medical uses

Abstract

Compstatin analogs having improved binding and complement inhibitory activity compared to the 13 amino acid compstatin peptide (ICVVQDWGHHRCT (C2 to C12 cyclization)) are described, particularly compstatin analogs that additionally have useful physicochemical properties, such as improved solubility. These analogs include variants having an isoleucine residue in place of the wild-type valine residue at position 3, which provides improved binding and complement inhibitory activity to the compstatin peptide and also enables the introduction of other modifications, such as modifications that can improve solubility, such as the introduction of a charged or polar amino acid at position 9, and / or the introduction of N-terminal and / or C-terminal sequences.

Description

Technical Field

[0001] The present invention relates to inhibiting the activation of the complement cascade in vivo, and more particularly to compstatin analogs that are capable of binding to the C3 protein and inhibiting complement activation. The present invention also relates to the medical use of compstatin analogs, in particular for the treatment of conditions characterized by undesired activation of the complement cascade, such as autoimmune diseases and inflammatory diseases. Background Art

[0002] The human complement system plays a powerful role in defending against pathogenic organisms and mediating immune responses. Complement can be activated by three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. The main activation event common to all three pathways is that the central protein C3 of the complement system is proteolytically cut into its activation products C3a and C3b by the C3 convertase. The production of these fragments causes pathogenic cells to be opsonized by C3b and iC3b (this is a process that makes them susceptible to phagocytosis or clearance), and immune cells are activated by interacting with complement receptors (Markiewski & Lambris, 2007, Am. J. Pathol., 171: 715-727). The deposition of C3b on target cells also induces the formation of new convertase complexes, thereby starting a self-amplification cycle. The collection of plasma and cell surface binding proteins carefully regulates the activation of complement to prevent host cells from being self-attacked by the complement cascade. However, excessive activation or inappropriate regulation of complement can lead to many pathological conditions ranging from autoimmune diseases to inflammatory diseases (Holers, 2003, Clin. Immunol., 107: 140-51; Markiewski & Lambris, 2007, supra; Ricklin & Lambris, 2007, Nat. Biotechnol., 25: 1265-75; Sahu et al., 2000, J. Immunol., 165: 2491-9). Therefore, the development of therapeutic complement inhibitors is highly desirable. In this context, C3 and C3b have become promising targets because their central role in the cascade allows for simultaneous inhibition of initiation, amplification, and downstream activation of complement (Ricklin & Lambris, 2007, supra).

[0003] Compstatin was originally identified as a 27 amino acid peptide and was the first non-host derived complement inhibitor shown to be able to block all three activation pathways (Sahu et al., 1996, J. Immunol., 157:884-91; U.S. Patent No: 6,319,897). It has been shown that compstatin can be truncated to a 13 amino acid peptide without loss of activity. However, attempts to further truncate the peptide resulted in loss of activity. The sequence of the 13 amino acid truncated (or "core") compstatin peptide is Ile 1 -Cys 2 -Val 3 -Val 4 -Gln 5 -Asp 6 -Trp7-Gly 8 -His 9 -His 10 -Arg 11 -Cys 12 -Thr 13 -NH2, where Cys 2 and Cys 12 The cyclic tridecapeptide binds to C3 (and fragments of C3), thereby inhibiting the activation of the downstream complement cascade and preventing the cleavage of native C3 by C3 convertase. A series of studies using experimental models have confirmed its inhibitory potency, pointing to its potential as a therapeutic agent (Fiane et al, 1999a, Xenotransplantation, 6:52-65; Fiane et al,, 1999b, Transplant Proc., 31:934-935; Nilsson et al, 1998, Blood, 92:1661-1667; Ricklin & Lambris, 2008, Adv. Exp. Med.. Biol., 632:273-292; Schmidt et al, 2003, J. Biomed. Mater. Res., A66:491-499; Soulika et al, 2000, Clin. Immunol., 96:212-221).

[0004] Stepwise optimization of the 13 amino acid compstatin peptide has led to analogs with improved biological activity (Ricklin & Lambris, 2008, supra; WO 2004 / 026328; WO 2007 / 062249, WO 2013 / 036778, WO 2014 / 100407).

[0005] Earlier structure-activity studies have identified the cyclic nature of the compstatin peptide and the presence of both a β-turn and a hydrophobic cluster as key features of the molecule (Morikis et al., 1998, Protein Sci., 7:619-627; WO 99 / 13899; Morikis et al., 2002, J. Biol. Chem., 277:14942-14953; Ricklin & Lambris, 2008, supra). The hydrophobic residues at positions 4 and 7 were found to be particularly important, and modification of these with unnatural amino acids produced analogs that were 264-fold more active than the original compstatin peptide (Katragadda et al., 2006, J. Med. Chem., 49:4616-4622; WO 2007 / 062249). Further attempts to optimize compstatin for the treatment of ocular diseases are described in WO 2007 / 044668.

[0006] Although previous optimization steps have been based on combinatorial screening studies, solution structures, and computational modeling (Chiu et al., 2008, Chem. Biol. Drug Des., 72:249-256; Mulakala et al., 2007, Bioorg. Med. Chem., 15:1638-1644; Ricklin & Lambris, 2008, supra), the publication of the co-crystal structure of compstatin in complex with complement fragment C3c (Janssen et al., 2007, J. Biol. Chem., 282:29241-29247; WO 2008 / 153963) provided a basis for initiating rational optimization. The crystal structure revealed a shallow binding site at the interface of macroglobulin (MG) domains 4 and 5 of C3c, and showed that 9 of the 13 amino acids are directly involved in binding through hydrogen bonds or hydrophobic interactions. Compared to the structure of the compstatin peptide in solution (Morikis et al., 1998, supra), the bound form of compstatin undergoes a conformational change, with the position of the β-turn shifting from residues 5-8 to 8-11 (Janssen et al., 2007, supra; WO 2008 / 153963).

[0007] Given their therapeutic potential in AMD, C3G, PNH and other diseases, further optimization of compstatin analogs, e.g., to obtain even greater activity and / or to modulate pharmacokinetic properties (e.g., improved in vivo half-life and / or physicochemical properties, such as increased solubility), remains a problem in the art. SUMMARY OF THE INVENTION

[0009] Broadly, the present invention is based on work to develop a new family of compstatin analogs that have improved binding and complement inhibitory activity compared to the 13 amino acid compstatin peptide (ICVVQDWGHHRCT (C2-C12 cyclization)). In some cases, these compstatin analogs additionally have useful physicochemical properties, such as improved solubility. In particular, the inventors have discovered that the introduction of an isoleucine residue at position 3 in place of the wild-type valine residue results in compstatin peptides with improved binding and complement inhibitory activity. The inventors have further discovered that the introduction of an isoleucine at position 3 enables the introduction of other modifications, such as modifications that can improve solubility, such as the introduction of glutamic acid at position 6, the introduction of specific charged or polar amino acids at position 9, and / or the introduction of N- and / or C-terminal sequences. Examples of such additional modifications include replacement of Ile at position 1 with Tyr, Phe, or Sar, replacement of VaI at position 4 with Trp, a Trp analog (as described herein); replacement of Asp at position 6 with Glu; replacement of His at position 9 with Ala, Glu, Asp, Lys, Ser, or Arg; replacement of Arg at position 11 with Ser; and replacement of Thr at position 13 with Ser, Glu, Sar, or Ile. For example, preferred compstatin peptides comprising one or more of these modifications have improved solubility compared to the 13 amino acid compstatin peptide (ICVVQDWGHHRCT (C2-C12 cyclization). Other examples of such compstatin peptides combine modification at position 9 with extensions of the N-terminus and / or C-terminus of the peptide.

[0010] Therefore, the present invention provides a compstatin analog represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0011] Y1-R1-X1-CI-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula I)

[0012] in:

[0013] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0014] X1 is I, Y, F or Sar;

[0015] X4 is W, F, V, Y, 1-Me-Trp, D-Trp, N-Me-Trp, 1-For-Trp, 1-Nal, 2-Nal, 5-Me-Trp, Bpa or 2-Igl;

[0016] X6 is E, K or D;

[0017] X8 is G or Sar;

[0018] X9 is H, A, E, D, K, R or S;

[0019] X11 is R, S or K;

[0020] X13 is T, S, E, F, H, K, Sar, G, I, D, N-Me-Ile or N-Me-Thr;

[0021] Y2 is NH2, OH or a lipophilic group Φ;

[0022] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0023] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0024] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0025] and wherein the compstatin analog optionally has a lipophilic group Φ covalently linked to the side chain of one or more amino acid residues.

[0026] In some embodiments, X11 is R or S.

[0027] In some embodiments, if the lipophilic group Φ is attached to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue at R1 or R2. It may be a lysine residue. For example, it may be a lysine residue at position X11 or X13, or a lysine residue at R1 or R2.

[0028] In some embodiments, Y1 is hydrogen or acetyl.

[0029] In some embodiments, Y2 is NH2 or OH.

[0030] In some embodiments, a compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0031] In some embodiments, a compstatin analog does not include a lipophilic group Φ.

[0032] The present invention further provides a compstatin analog represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0033] Y1-R1-X1-CI-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula II)

[0034] in:

[0035] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0036] X1 is I, Y, F or Sar;

[0037] X4 is W, V, Y, 2-Nal, 1-Nal or 1-Me-Trp;

[0038] X6 is E or D;

[0039] X8 is G or Sar;

[0040] X9 is A, E, D, K or S;

[0041] X11 is R, S or K;

[0042] X13 is T, S, E, I, Sar, K, G, or N-Me-Ile;

[0043] Y2 is NH2, OH or a lipophilic group Φ;

[0044] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0045] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0046] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0047] and wherein the compstatin analog optionally has a lipophilic group Φ covalently attached to the side chains of one or more amino acids.

[0048] In some embodiments, X11 is R or S.

[0049] In some embodiments, if the lipophilic group Φ is attached to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue at R1 or R2. It may be a lysine residue, for example, it may be a lysine residue at position X13, or a lysine residue at R1 or R2.

[0050] In some embodiments, Y1 is hydrogen or acetyl.

[0051] In some embodiments, Y2 is NH2 or OH.

[0052] In some embodiments, a compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0053] In some embodiments of this formula, the compstatin analog does not include a lipophilic group Φ.

[0054] The present invention further provides a compstatin analog represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0055] Y1-R1-X1-CI-X4-Q-X6-WG-X9-H-X11-C-X13-R2-Y2 (Formula III)

[0056] in:

[0057] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0058] X1 is I, Y, F or Sar;

[0059] X4 is W, V, Y, 1-Nal, 2-Nal or 1-Me-Trp;

[0060] X6 is E or D;

[0061] X9 is A, E, D, K or S;

[0062] X11 is R, S or K;

[0063] X13 is T, I, S, E, K or Sar;

[0064] Y2 is NH2, OH or a lipophilic group Φ;

[0065] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0066] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0067] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0068] and wherein the compstatin analog optionally has a lipophilic group Φ covalently attached to the side chains of one or more amino acids.

[0069] In some embodiments, X11 is R or S.

[0070] In some embodiments, if the lipophilic group Φ is attached to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue at R1 or R2. It may be a lysine residue, for example, it may be a lysine residue at position X11 or X13, or a lysine residue at R1 or R2.

[0071] In some embodiments, Y1 is hydrogen or acetyl.

[0072] In some embodiments, Y2 is NH2 or OH.

[0073] In some embodiments, a compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0074] In some embodiments of this formula, the compstatin analog does not include a lipophilic group Φ.

[0075] A compstatin analog may be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0076] Y1-R1-X1-CI-X4-Q-X6-WG-X9-HRC-X13-R2-Y2 (Formula IV)

[0077] in:

[0078] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0079] X1 is I, Y, F or Sar;

[0080] X4 is W, V, Y, 1-Nal, 2-Nal or 1-Me-Trp;

[0081] X6 is E or D;

[0082] X9 is A, E, D, K or S;

[0083] X13 is T, S, E or Sar;

[0084] Y2 is NH2, OH or a lipophilic group Φ;

[0085] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0086] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0087] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0088] and wherein the compstatin analog optionally has a lipophilic group Φ covalently attached to the side chains of one or more amino acids.

[0089] In some embodiments, if the lipophilic group Φ is attached to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue at R1 or R2. It may be a lysine residue, for example, it may be a lysine residue at position X13, or a lysine residue at R1 or R2.

[0090] In some embodiments, Y1 is hydrogen or acetyl.

[0091] In some embodiments, Y2 is NH2 or OH.

[0092] In some embodiments, a compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0093] In some embodiments of this formula, the compstatin analog does not include a lipophilic group Φ.

[0094] In some embodiments of the above formula, X6 is D.

[0095] In one aspect, a compstatin analog without a lipophilic group Φ can be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0096] Y1-R1-X1-CI-X4-Q-X6-WG-X9-HRC-X13-R2-Y2 (Formula V)

[0097] in:

[0098] Y1 is hydrogen or acetyl;

[0099] X1 is Y or F;

[0100] X4 is W, Y, 1-Me-Trp;

[0101] X6 is E or D;

[0102] X9 is A, E or K;

[0103] X13 is T, E or Sar;

[0104] Y2 is NH2 or OH;

[0105] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0106] R2 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0107] Compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12.

[0108] A compstatin analog may be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0109] Y1-R1-X1-CI-(1-Me-Trp]-Q-X6-WGEHRC-X13-R2-Y2 (Formula VI)

[0110] in:

[0111] Y1 is hydrogen or acetyl;

[0112] X1 is Y or F;

[0113] X6 is E or D;

[0114] X13 is T, E or Sar;

[0115] Y2 is NH2 or OH;

[0116] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof; and

[0117] R2 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or the corresponding D forms thereof; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0118] Compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12.

[0119] In the above formula, X6 may be D. Alternatively, it may be E.

[0120] In some embodiments, the compstatin analog has the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0121] Y1-R1-X1-CI-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula VII)

[0122] in:

[0123] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0124] X1 is I, Y, F or Sar;

[0125] X4 is W, V, 1-Me-Trp, 1-Nal or 2-Nal;

[0126] X6 is E, K or D;

[0127] X8 is G or Sar;

[0128] X9 is H, A, E, D, K, R or S;

[0129] X11 is R, S, K, or K*;

[0130] X13 is T, S, E, Sar, or N-Me-Ile;

[0131] Y2 is NH2 or OH;

[0132] R1 and R2 may be as defined in any of the above formulas or elsewhere in this specification. In some embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, K, K*, S, Y or their corresponding D forms; and / or R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, K, K*, P, S, Peg3, γGlu, 8-aminooctanoyl or their corresponding D forms;

[0133] Wherein * indicates that the amino acid residue has a lipophilic group Φ covalently attached to its side chain.

[0134] It may be desirable for a compstatin analog to include at least one lipophilic group Φ, such as exactly one lipophilic group Φ. Alternatively, it may include no lipophilic group Φ.

[0135] In another aspect, a compstatin analog comprising a lipophilic group Φ can be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0136] Y1-R1-X1-CI-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula VIII)

[0137] in:

[0138] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0139] X1 is I, Y, F or Sar;

[0140] X4 is W, V, Y, 2-Nal, 1-Nal or 1-Me-Trp;

[0141] X6 is E or D;

[0142] X8 is G or Sar;

[0143] X9 is A, E, D, K or S;

[0144] X11 is R, S, or K*;

[0145] X13 is T, S, E, I, Sar, K, G, or N-Me-Ile;

[0146] Y2 is NH2, OH or a lipophilic group Φ;

[0147] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, K*, F, P, S, T, W, Y, R, V or Sar, or the corresponding D forms;

[0148] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V Sar, εLys, γGlu, βAsp or βAla, their corresponding D forms; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0149] Wherein * indicates that the amino acid residue has a lipophilic group Φ covalently linked to its side chain;

[0150] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0151] and wherein the compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0152] In some embodiments, Y2 is NH2 or OH.

[0153] A compstatin analog may be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0154] Y1-R1-X1-CI-X4-Q-X6-WG-X9-H-X11-C-X13-R2-Y2 (Formula IX)

[0155] in:

[0156] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0157] X1 is I, Y, F or Sar;

[0158] X4 is W, V, Y, 1-Nal, 2-Nal or 1-Me-Trp;

[0159] X6 is E or D;

[0160] X9 is A, E, D, K or S;

[0161] X11 is R, S, or K*;

[0162] X13 is T, I, S, E, K or Sar;

[0163] Y2 is NH2, OH or a lipophilic group Φ;

[0164] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, K*, F, P, S, T, W, Y, R, V or Sar, or the corresponding D forms;

[0165] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, K*F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, their corresponding D forms; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0166] Wherein * indicates that the amino acid residue has a lipophilic group Φ covalently attached to its side chain.

[0167] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0168] and wherein the compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0169] In some embodiments, Y2 is NH2 or OH.

[0170] A compstatin analog may be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0171] Y1-R1-X1-CI-X4-Q-X6-WG-X9-HRC-X13-R2-Y2 (Formula X)

[0172] in:

[0173] Y1 is hydrogen, acetyl or a lipophilic group Φ;

[0174] X1 is I, Y, F or Sar;

[0175] X4 is W, V, 1-Nal, 2-Nal or 1-Me-Trp;

[0176] X6 is E or D;

[0177] X9 is A, E, D, K or S;

[0178] X13 is T, S, E or Sar;

[0179] Y2 is NH2, OH or a lipophilic group Φ;

[0180] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, K*, F, P, S, T, W, Y, R, V or Sar, or the corresponding D forms;

[0181] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, K*, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, their corresponding D forms; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0182] Where * indicates that the amino acid residue has a lipophilic group Φ covalently attached to its side chain;

[0183] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0184] and wherein the compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0185] In some embodiments, Y2 is NH2 or OH.

[0186] In any of the above formulae, X6 may be D. Alternatively, X6 may be E.

[0187] In any of the above formulae, X1 may be Y. Alternatively, X1 may be F.

[0188] In any of the above formulae, X13 may be Sar. Alternatively, X13 may be T.

[0189] Additionally or alternatively, any of the above formulae may contain one of the following residue combinations:

[0190] X4 is 1-Me-Trp, and X9 is E.

[0191] X1 is F, X4 is 1-Me-Trp, and X9 is E.

[0192] X4 is 1-Me-Trp, X9 is E, and X13 is Sar.

[0193] X4 is 1-Me-Trp, X9 is E, and X13 is T.

[0194] X4 is 1-Me-Trp, X6 is D, X9 is E, and X13 is Sar.

[0195] X4 is 1-Me-Trp, X6 is E, X9 is E, and X13 is Sar.

[0196] X4 is 1-Me-Trp, X6 is D, X9 is E, and X13 is T.

[0197] X4 is 1-Me-Trp, X6 is E, X9 is E, and X13 is T.

[0198] A compstatin analog may be represented by the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0199] Y1-R1-X1-CI-[1-Me-Trp]-Q-X6-WGEHRC-X13-R2-Y2 (Formula XI)

[0200] in:

[0201] Y1 is hydrogen or acetyl;

[0202] X1 is Y or F;

[0203] X6 is E or D;

[0204] X13 is T, E or Sar;

[0205] Y2 is NH2 or OH;

[0206] R1 is absent or is a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, L, K, K*, F, P, S, T, W, Y, R, V or Sar, or the corresponding D forms;

[0207] R2 is absent or is a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, K*F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, their corresponding D forms; or Peg3 or Peg4 or 8-aminooctanoyl, or a derivative thereof;

[0208] Wherein * indicates that the amino acid residue has a lipophilic group Φ covalently attached to its side chain.

[0209] Wherein compstatin analogs have a disulfide bond between the cysteine ​​residues at positions 2 and 12;

[0210] and wherein the compstatin analog comprises at least one lipophilic group Φ, such as exactly one lipophilic group Φ.

[0211] In some embodiments, the 13-mer peptide portion (X1-X13) of the compstatin analog has a sequence selected from the group consisting of:

[0212] [Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar];

[0213] [Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)T;

[0214] [Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)T;

[0215] [Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar];

[0216] [Sar]C(1)IWQDWGEHRC(1)T;

[0217] FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar];

[0218] FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)T;

[0219] FC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar];

[0220] FC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar];

[0221] FC(1)I[1-Me-Trp]QDWGEHRC(1)E;

[0222] FC(1)I[1-Me-Trp]QDWGEHRC(1)S;

[0223] FC(1)I[1-Me-Trp]QDWGEHRC(1)T;

[0224] FC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar];

[0225] FC(1)I[1-Nal]QDWGEHRC(1)T;

[0226] FC(1)I[2-Nal]QDWGEHRC(1)T;

[0227] FC(1)IWQDWGEHRC(1)[Sar];

[0228] FC(1)IWQDWGEHRC(1)T;

[0229] IC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)[N-Me-Ile];

[0230] IC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar];

[0231] IC(1)I[1-Me-Trp]QDWGEHRC(1)T;

[0232] IC(1)I[2-Nal]QDWGEHRC(1)[Sar];

[0233] IC(1)IWQDWGAHRC(1)E;

[0234] IC(1)IWQDWGAHRC(1)T;

[0235] IC(1)IWQDWGAHSC(1)T;

[0236] IC(1)IWQDWGDHRC(1)T;

[0237] IC(1)IWQDWGEHRC(1)[Sar];

[0238] IC(1)IWQDWGEHRC(1)E;

[0239] IC(1)IWQDWGEHRC(1)S;

[0240] IC(1)IWQDWGEHRC(1)T;

[0241] IC(1)IWQDWGEHSC(1)T;

[0242] IC(1)IWQDWGKHRC(1)T;

[0243] IC(1)IWQDWGRHRC(1)T;

[0244] IC(1)IWQDWGSHRC(1)T;

[0245] IC(1)IWQEWGEHRC(1)T;

[0246] IC(1)IWQKWGAHRC(1)T;

[0247] IC(1)IWQKWGEHRC(1)T;

[0248] YC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar];

[0249] YC(1)I[1-Me-Trp]QDWGEHRC(1)T;

[0250] YC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar];

[0251] YC(1)I[2-Nal]QDWGEHRC(1)T;

[0252] YC(1)IWQDWGEHRC(1)T;

[0253] YC(1)I[1-Me-Trp]QDWGEH[K ＊ ]C(1)[Sar]; and

[0254] YC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar];

[0255] Wherein * indicates that the amino acid residue has a lipophilic group Φ covalently attached to its side chain.

[0256] In some embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, R, V or Sar or the corresponding D forms and / or R2 can be a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, R, V or Sar or the corresponding D forms.

[0257] For example, R1 is selected from ESSA, AKGE, ASSE, ASES, GSAE, ESSE, ESGA, SEG, GES, ESS, EGSA, ESE, EGE, ESA, SAE, SGA, YLEA, GSA, KEK, EKG, ES, AS, SE, SA or E, and / or R2 is selected from GAE S, EYGS, EGYA, EAGS, EAKS, EKSA, EGGS, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, ESG, EAG, GAE, EGEA, EGE, EA, E, GE, EG, EKE or EKP.

[0258] In some alternative embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from: A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or their corresponding D forms, or Peg3, Peg4 or 8-aminooctanoyl, or a derivative thereof.

[0259] In some embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V or Sar, or the corresponding D forms thereof.

[0260] For example, R1 may be absent or a sequence of 1 to 6 amino acid residues selected from the group consisting of A, E, G, K, S and Y or their corresponding D forms.

[0261] The lipophilic group Φ may be covalently linked to the side chain of one or more residues in Y1, in particular to the side chain of a lysine residue (which may be referred to as K*). It may be desirable for the residue having Φ to be at the N-terminus of Y1.

[0262] Examples of sequences of the group R1 include:

[0263] {d}Y, EGSE, AGSE, SASE, EYSE, GSE, ASE, ESSA, KGSA, AKGE, ASGE, ASSE, ASES, GSAE, ESSE, ESGA, SEG, GES, ESS, E GSA, ESE, EGE, ESA, SAE, SGA, YLEA, GSA, KEK, EKG, ES, RS, SR, AE, TE, KE, GE, FE, YE, AS, SE, RS, SR, SA, GE, S, Y, and E.

[0264] In some embodiments, R1 is two amino acid residues in length, e.g., AE, TE, KE, GE, FE, YE, AS, SE, SA or GE; preferably AE, TE, KE, GE, FE, YE, SE or GE.

[0265] In some embodiments, R1 is one amino acid in length, such as E.

[0266] As described above, the lipophilic group Φ may be covalently linked to the side chain of one or more residues in Y1, in particular to the side chain of a lysine residue (which may be referred to as K*), for example to produce the sequence K*GSA.

[0267] R2 may be absent or a sequence of 1 to 8 amino acid residues selected from the group consisting of A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp or βAla, or their corresponding D forms; or Peg3, Peg4, or 8-aminooctanoyl, or a derivative thereof.

[0268] For example, R2 may be absent or may be a sequence of 1 to 8 amino acid residues selected from A, E, G, K, S, γGlu, Peg3 or 8-aminooctanoyl or selected from A, E, G, K and S.

[0269] When K is present in R2, it is desirable that K is present at the C-terminus of R2.

[0270] The lipophilic group Φ may be covalently linked to the side chain of one or more residues in Y2, in particular to the side chain of a lysine residue. It may be desirable for the residue carrying Φ to be located at the C-terminus of Y2.

[0271] Examples of sequences of the group R2 include:

[0272] EGASGSG, EGAGSG, EGASAG, EGAGAG, EGESGSG, EGEGSG, EGESAG, EGEGAG, EK[γGlu]AK, EGEGG, EGAGG, EGESS, GAESK, EGAK, EGEK, EGG, EGK, EGKK, EGS, EK, EGA, EGAK, EK[γGlu], EK[γGlu]-K, EGE-[Peg3, EGE[Peg3]-K, EGE[Peg3][Peg3], EGE[Peg3][Peg3]-K, EGE[Peg3][Peg3][Peg3], GESESE, GAESES, EGESES, EGESESK, EGE[Peg3]-ES, EGE[Peg3]-ESK, GESESE, EGE-[8-aminooctanoyl], EGE-[8-aminooctanoyl]-K, EGE-[8-aminooctanoyl]-EK, EGEGGG, EGEGGGK, EK[γGlu]GGG, EK[γGlu]GGGK, EGE-[8-aminooctanoyl]-E, GAES, EYGS, EGYA, EAGS, EAKS, EKSA, ESGA, EGG, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, EGK,, ESG, EAG, GAE, EGEA, EGE, EA, E, S, GE, GEK, EG, EA, EKE and EKP.

[0273] Examples of the sequence of group R2 include:

[0274] EGASGSG、EGAGSG、EGASAG、EGAGAG、EGESGSG、EGEGSG、EGESAG、EGEGAG、EK[γGlu]AK、EK[γGlu]A、EGEGG、EGAGG、EGESS、GAESK、EGAK、EGEK、EGG、EGK、EGKK、EGS、EK、EGA、EGAK、EK[γGlu]、EK[γGlu ]-K、EGE[Peg3]、EGE[Peg3]-K、EGE[Peg3][Peg3]、EGE[Peg3][Peg3]-K、EGE[Peg3][Peg3][Peg3]、EGE[Peg3][Peg3][Peg3]-KGESESE、GAESES、EGESES、EGESESK、EGE[Peg3]-ES、EGE[Peg3]-E SK、GESESE、EGE-[8-aminoacid]、EGE-[8-aminoacid]-K、EGE-[8-aminoacid]-EK、EGEGGG、EGEGGGK、EK[γGlu]GGG、EK[γGlu]GGGK、EGE-[8-aminoacid]-E、E[Peg3][Peg3]、E[Peg3][Peg3]-K、EA[Peg3][Peg3]、 EA[Peg3][Peg3]-K, GAES, EYGS, EGYA, EAGS, EAKS, EKSA, ESGA, EGGS, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, EGK, ESG, EAG, GAE, EGEA, EGE, EA, E, S, GE, GEK, EG, EA, EKE and EKP.

[0275] As mentioned above, the side chain of one or more residues in Y2, especially the side chain of a lysine residue, can be covalently linked, for example, from the sequence EK[γGlu]AK*, EGKK*, EK[γGlu]K*, EGE[Peg3]-K*, EGESESK*, EGE[Peg3]-ESK*, EGE-[8- Amino acid]-K*、EGE-[8-amino acid]-EK*、EGEGGGK*、EK[γGlu]GGGK*、EGE[Peg3][Peg3]-K*、GAESK*、EGAK*、EGEK*、EGK*EGE[Peg3]-ESK*、GESEK*、GEK* or EK*.

[0276] As described above, the lipophilic group Φ can be covalently linked to the side chain of one or more residues in Y2, in particular the side chain of a lysine residue, for example to produce the sequence EK[γGlu]AK*, EGKK*, EK[γGlu]K*, EGE[Peg3]-K*, EGEESK*, EGE[Peg3]-ESK*, EGE-[8-aminooctanoyl]-K*, EGE-[8-aminooctanoyl]-EK*, EGEGGGK*, EK[γGlu]GGGK*, EGE[Peg3][Peg3]-K*, EGE[Peg3][Peg3][Peg3]-K*, E[Peg3][Peg3]-K*, EA[Peg3][Peg3]-K*, GAESK*, EGAK*, EGEK*, EGK*EGE[Peg3]-ESK*, GESESEK*, GEK* or EK*.

[0277] When R1 or R2 is one amino acid in length, it may be a D amino acid, such as {d}Y.

[0278] R1 and R2 may be present or absent independently. It may be desirable for R2 to be present. Without wishing to be bound by any particular theory, it is believed that the presence of R1 and / or R2 may improve the stability of the compound.

[0279] Classes of preferred compstatin analogs and exemplary compounds are discussed further below.

[0280] In another aspect, the invention provides a composition comprising a compstatin analog of the invention, or a pharmaceutically acceptable salt or solvate thereof, mixed with a carrier. In some cases, the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

[0281] In another aspect, the invention provides a pharmaceutical composition comprising a compstatin analog of the invention, or a pharmaceutically acceptable salt or solvate thereof, admixed with a pharmaceutically acceptable carrier, excipient, or vehicle.

[0282] In another aspect, the invention provides a compstatin analog of the invention for use in therapy.

[0283] In another aspect, the invention provides compstatin analogs of the invention for use in a method of inhibiting complement activation. As an example, inhibiting complement activation comprises one or more biological activities selected from: (1) binding to C3 protein, (2) binding to C3b protein, and / or (3) inhibiting cleavage of native C3 by C3 convertase. Some examples of diseases or conditions that can be treated using compstatin analogs of the invention are discussed below.

[0284] In another aspect, the invention provides a compstatin analog of the invention for use in a method of inhibiting complement activation that occurs during cell or organ transplantation.

[0285] In another aspect, the invention provides methods of inhibiting complement activation for use in treating a subject in need thereof, the method comprising administering to the subject a compstatin analog of the invention, thereby inhibiting complement activation in the subject. Some examples of diseases or conditions that can be treated using compstatin analogs of the invention are discussed below.

[0286] In another aspect, the invention provides an ex vivo method of inhibiting complement activation during diversion of a physiological fluid in vitro, the method comprising contacting the physiological fluid with a compstatin of the invention, thereby inhibiting complement activation.

[0287] In another aspect, the invention provides use of a compstatin analog of the invention in the preparation of a medicament for inhibiting complement activation.Some examples of diseases or conditions that can be treated using compstatin analogs of the invention are discussed below.

[0288] Embodiments of the invention will now be described by way of example and not limitation. BRIEF DESCRIPTION OF THE DRAWINGS

[0289] Figure 1 (a to f): Normalized alternative complement pathway "ex vivo" activity over time following administration of a test compound to one or two non-human primates at time 0. Compounds were administered subcutaneously at a dose of 1840 nmol / kg. Complement activity (alternative pathway) was measured using the Wieslab kit. Activity was normalized using the pre-dose (0) sample (set to 100%) and the negative control included in the kit. Normalized activity or the average normalized activity of two animals and standard deviation are shown. (a) Compound 61 (2 animals), (b) Compound 123, Compound 126 and Compound 128 (all one animal for each compound) and Cp40 (2 animals), (c) Compound 107, Compound 111, Compound 118 and Compound 119 (all 2 animals for each compound), (d) Compound 104 and Compound 106 (2 animals for each compound), (e) Compound 54 (2 animals) and Compound 122, Compound 124, Compound 139 and Compound 140 (all 1 animal for each compound), and (f) Compound 141, Compound 142, Compound 127 and Compound 130 (all one animal for each compound). DETAILED DESCRIPTION OF THE INVENTION

[0291] As used herein, "and / or" should be considered as specific disclosure of each of two specific features or components with or without the other. For example, "A and / or B" should be considered as specific disclosure of each of (i) A, (ii) B, and (iii) A and B, just as if each were listed separately herein.

[0292] Unless the context dictates otherwise, the descriptions and definitions of the features listed above are not limited to any particular aspect or embodiment of the invention, and apply equally to all aspects and embodiments described.

[0293] Various publications, including patents, published applications, technical articles, and academic articles, are cited throughout the specification. Each of these cited publications is incorporated herein by reference in its entirety.

[0294] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally speaking, the nomenclature and techniques used in connection with the chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0295] Each embodiment of the present invention described herein may be used alone or in combination with one or more other embodiments of the present invention.

[0296] Unless otherwise indicated, the following definitions are provided for specific terms used in this written description.

[0297] definition

[0298] Throughout this specification, the word "comprise" and grammatical variations (e.g., "comprises" or "comprising") will be understood to mean including / comprising the specified integer or components or groups of integers or components but not excluding any other integer or component or groups of integers or components.

[0299] Unless the context clearly dictates otherwise, a noun without a quantifier means one or more than one.

[0300] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0301] The terms "patient," "subject," and "individual" are used interchangeably. A subject can be a mammal, including a human or a non-human mammal, such as a non-human primate (e.g., an ape, an Old World monkey, or a New World monkey), a livestock animal (e.g., a cow or pig), a companion animal (e.g., a dog or a cat), or an experimental animal such as a rodent (e.g., a mouse or a rat).

[0302] Throughout the specification and claims, the conventional three-letter and one-letter codes for naturally occurring amino acids are used, i.e., A (Ala), G (Gly), L (Leu), I (Ile), V (Val), F (Phe), W (Trp), S (Ser), T (Thr), Y (Tyr), N (Asn), Q (Gln), D (Asp), E (Glu), K (Lys), R (Arg), H (His), M (Met), C (Cys), and P (Pro); as well as the commonly accepted three-letter codes for other α-amino acids, such as norleucine (Nle), sarcosine (Sar), α-aminoisobutyric acid (AABA), and α-aminoisobutyric acid (AIP). (Aib), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab) and 2,5-diaminopentanoic acid (ornithine; Orn), 1-methyltryptophan (1-Me-Trp, 1Me-Trp or 1MeTrp), 1-formyltryptophan (1-For-Trp or 1For-Trp or 1ForTrp), 1-naphthol (1-Nal or 1Nal), 2-naphthol (2-Nal or 2Nal), 5-methyltryptophan (5-Me-Trp or 5Me-Trp or 5MeTrp), p-benzoyl-phenylalanine (Bpa) 2-indanylglycine (2Igl or 2-Igl). When used in the general formula or sequence in the present specification, especially when the rest of the formula or sequence is shown using a single letter code, other α-amino acids may be shown in square brackets "[]" (e.g., "[Nle]"). The 20 "naturally occurring" amino acids listed above are those encoded by the standard genetic code, and may also be referred to as "proteinogenic" amino acids.

[0303] γ-Glu and β-Asp, also known as γGlu (γ-Glu) and βAsp (β-Asp) (or isoGlu and isoAsp), refer to glutamic acid or aspartic acid participating in a peptide bond via a γ- or β-carboxylic acid (usually considered to be a side chain carboxyl group), respectively, rather than the conventional configuration. Similarly, εLys or isoLys refers to lysine participating in a peptide bond via an ε amino group (usually considered to be a side chain amino group) rather than an α amino group.

[0304] β-Ala, also known as β-Ala or βAla, refers to 3-aminopropionic acid.

[0305] Peg3 refers to the residue of 8-amino-3,6-dioxaoctanoic acid (also known as {2-[2-aminoethoxy]ethoxy}acetic acid), and Peg4 refers to the residue of 11-amino-3,6,9-trioxaundecanoic acid. This residue can also be represented as [8-amino-3,6-dioxaoctanoyl].

[0306] 8-Amino-3,6-dioxaoctanoic acid (Peg3)

[0307] Unless otherwise indicated, the amino acid residues in the peptides of the present invention have an L-configuration. However, in some cases, D-configuration amino acids may be incorporated. In this context, the amino acid code written in lowercase letters represents the amino acid in the D-configuration, for example, "k" represents lysine (K) in the D-configuration, or the D-configuration amino acid may be written as (d)X or {d}X, where X is an amino acid, for example (d)Y or {d}Y represents tyrosine (Y) in the D-configuration.

[0308] A cysteine ​​residue designated as "C(1)" indicates that its side chain participates in a disulfide bond. Thus, there will usually be two such residues in any given molecule.

[0309] The terminal groups present at the N-terminus and C-terminus of the peptide backbone are named Y1 and Y2, respectively. Thus, Y1 is bonded to the nitrogen atom of the N-terminal amino group, and Y2 is bonded to the C-terminal carbonyl carbon atom.

[0310] Y1 = Hydrogen (also indicated as "H-" or "Hy-") represents a hydrogen atom, which corresponds to the presence of a free primary or secondary amino group at the N-terminus. Y1 = Acetyl ("Ac") represents the presence of an N-terminal secondary acetylamide group.

[0311] Y2="OH" or "NH2" indicates the presence of a carboxyl (COOH) group or an amide (CONH2) group at the C-terminus of the molecule.

[0312] Alternatively, either or both of Y1 and Y2 may be a lipophilic group Φ. Typically, only one of Y1 or Y2 is a lipophilic group Φ.

[0313] In some embodiments, whether or not the molecule contains a lipophilic group elsewhere, Y2 is NH2 or OH. In some embodiments, Y1 is hydrogen or acetyl, and Y2 is OH or NH2.

[0314] In some embodiments, whether or not the molecule contains a lipophilic group elsewhere, Y2 is NH2. In some embodiments, Y1 is hydrogen or acetyl, and Y2 is NH2.

[0315] In some embodiments, whether or not the molecule contains a lipophilic group elsewhere, Y2 is NH2 and Y1 is acetyl.

[0316] Multiple terms related to the method and other aspects of the present invention are used throughout the specification and claims. Unless otherwise indicated, these terms have their ordinary meaning in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein. The term "about" as used herein, when relating to measurable values ​​(such as amounts, durations, etc.), means to cover ± 20% or ± 10% of a specific value, ± 5% in some embodiments, ± 1% in some embodiments, and ± 0.1% of a change in some embodiments, because such changes are suitable for preparing and using disclosed compounds and compositions.

[0317] As used herein, the term "full-length compstatin" refers to a 27 amino acid peptide having the sequence IC(1)VVQDWGHHRC(1)TAGHMANLTSHASAI, wherein C(1) represents a cysteine ​​residue linked by a disulfide bond. As described above, a truncated form of full-length compstatin, the tridecapeptide Ile is linked by a disulfide bond between the cysteine ​​residues at positions 2 and 12. 1 -Cys2-Val 3 -Val4-Gln 5 -Asp 6 -Trp 7 -Gly 8 -His 9 -His 10 -Arg 11 -Cys 12 -Thr 13 -NH2 retains the activity of the full-length peptide. The N-terminally acetylated form of this tridecapeptide is referred to herein as "Ac-comstatin."

[0318] The term "comstatin analog" refers to modified Ac-comstatin that includes one or more substitutions of natural and non-natural amino acids or amino acid analogs, as well as modifications within or between various amino acids, as described in more detail herein. A compstatin analog may include about 1, 2, 3, 4, or 5 amino acid modifications relative to Ac-comstatin. A compstatin analog may include 5, 6, 7, 8, or more amino acid modifications relative to Ac-comstatin. A compstatin analog may include about 5, 6, 7, or 8 amino acid modifications relative to Ac-comstatin.

[0319] The term "analog" is often used for the protein or peptide in question before further chemical modification (derivation) and in particular acylation of the protein or peptide in question. The products resulting from such chemical modification (derivation) are sometimes referred to as "derivatives" or "acylated analogs". However, in the context of the present application, the term "analog" refers to analogs of Ac-comstatin as well as (acylated) derivatives of such Ac-comstatin analogs.

[0320] When referring to the position of an amino acid or analog in Ac-comstatin or a compstatin analog, the position is numbered from 1 (Ile in compstatin) to 13 (Thr in compstatin). For example, a Gly residue occupies "position 8". "C(1)" used to describe a compstatin analog peptide of the invention indicates a disulfide bond between cysteine ​​residues in a compstatin analog.

[0321] The terms "pharmaceutically active" and "biologically active" refer to the ability of a compound of the invention to bind to C3 or a fragment thereof and inhibit complement activation. The biological activity of a compstatin analog can be measured by one or more of several art-recognized assays, as described in more detail herein.

[0322] As used herein, "L-amino acid" refers to any naturally occurring left-handed α-amino acid commonly found in proteins or the alkyl esters of those α-amino acids. The term "D-amino acid" refers to a right-handed α-amino acid. Unless otherwise indicated, all amino acids referred to herein are L-amino acids.

[0323] "Hydrophobic" or "non-polar" are used synonymously herein and refer to any inter- or intra-molecular interaction that is not characterized by a dipole.

[0324] As used herein, "pharmaceutically acceptable salts" refer to derivatives of disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali metal or organic salts of acidic residues (e.g., carboxylic acids); and the like. Thus, the term "acid addition salt" refers to the corresponding salt derivative of the parent compound prepared by the addition of an acid. Pharmaceutically acceptable salts include, for example, conventional salts or quaternary ammonium salts of the parent compound formed from inorganic or organic acids. For example, such conventional salts include, but are not limited to, those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and the like. Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acids, free bases, and zwitterions are contemplated within the scope of the present invention.

[0325] Compstatin analogs

[0326] Ac-comstatin is an N-terminally acetylated 13 amino acid peptide known to bind to C3 and prevent C3 convertase-mediated cleavage. Since its discovery by phage display, the 13 amino acid Ac-comstatin sequence has been modified to search for analogs with improved biological activity. However, in the core sequence between the two cysteine ​​residues at positions 2 and 12, alanine scanning experiments have previously produced analogs that showed only modest improvements in biological activity, with few modifications being tolerated. Modifications included changing the valine at position 4 to tryptophan or a tryptophan analog (which resulted in improved biological activity), and changing the histidine at position 9 to alanine or its analog.

[0327] In particular, it has been shown that previous attempts to introduce modifications to the valine residue at position 3, replacing it with glycine, alanine, D-valine or leucine, resulted in reduced biological activity. In contrast to these prior art findings, the present inventors have surprisingly found that a change from valine to isoleucine is well tolerated and provides an improvement in biological activity, as shown in the following examples.

[0328] Without wishing to be bound by any particular theory, the inventors believe that this modification can be combined with the introduction of one or more polar or charged amino acids in the core sequence and can be used as a method to improve the solubilizing ability of compstatin peptides. Initially, glutamic acid or serine at position 9 was combined with valine 3 and resulted in reduced activity compared to the reference sequence 4W9A. However, when these changes were combined with the introduction of isoleucine at position 3, a surprising increase in biological activity was observed, particularly for the combination of isoleucine at position 3 and glutamic acid at position 9. This observation correlated with improved binding to C3, as measured by surface plasmon resonance (SPR), see Table 7.

[0329] In a further series of experiments used to validate these findings, compstatin peptides with glutamic acid at position 9 were combined with different substitutions in position 3 (which is generally considered a "conservative" replacement for isoleucine), again showing that peptides with isoleucine at position 3 were the most active.

[0330] Taken together, these experiments demonstrate that replacing the valine residue at position 3 with isoleucine unexpectedly provides compstatin peptides with increased biological activity and improved binding to C3. Furthermore, the experiments unexpectedly show that these changes can be easily combined with other modifications in the core sequence of compstatin analogs and with additions of N- and C-terminal sequences, e.g., to improve the solubility of the compstatin peptide, e.g., at higher concentrations.

[0331] Introduction of isoleucine instead of valine at position 3 of another prior art compound called "Cp40" (Qu et al., Immunobiology 2013, 281(4):496-505; also referred to in that paper as "peptide 14") also improved binding affinity to C3 as measured by SPR.

[0332] In any embodiment, X1 can be Y, I or F. In any embodiment, X4 can be W, V, 1-Nal, 2-Nal or 1-Me-Trp. In any embodiment, X6 can be E or D. In any embodiment, X9 can be A, E, D, K or S. In any embodiment, X13 can be T, S, E, I, Sar, K or G. In any embodiment, X13 can be T, I, S, E, K or Sar. In any embodiment, X13 can be T, S, E or Sar.

[0333] Lipophilic Substituents

[0334] Compstatin analogs may carry a lipophilic group, termed Φ.

[0335] The lipophilic group may be covalently linked to the N-terminus and / or the C-terminus of the molecule, ie Y1 may be Φ (instead of H or Ac) and / or Y2 may be Φ (instead of OH or NH2).

[0336] Additionally or alternatively, the lipophilic group may be covalently linked to the side chain of an amino acid residue in the analog. The residue may be part of R1, R2, or a compstatin analog moiety X1-X13 of the molecule.

[0337] The lipophilic group Φ is usually attached via an acyl group. This modification can therefore be referred to as acylation, but can also be referred to as lipidation.

[0338] The lipophilic group includes a long chain alkylene group (referred to herein as Z 1 ), and are referred to as lipophilic substituents. Without wishing to be bound by theory, it is believed that lipophilic substituents bind plasma proteins (e.g., albumin) in the bloodstream, thereby protecting the compounds used in the context of the present invention from enzymatic degradation and thereby extending the half-life of the compounds. Lipophilic substituents may also modulate the potency of the compound.

[0339] Z 1 The amino acid sequence (including R1 and R2 extension, or as Y1) may be directly linked or via a spacer Z as defined herein. 2 connect.

[0340] In other words, Φ can be Z 1 - or Z 1 -Z2 -.

[0341] When Y1 is Φ, Φ is preferably Z 1 -.

[0342] When the lipophilic group Φ is attached to an amino acid side chain (ie, Y1 is hydrogen or Ac), Φ may preferably be Z 1 -Z 2 -.

[0343] In certain embodiments, only one amino acid side chain is conjugated to a lipophilic substituent. In other embodiments, two amino acid side chains are each conjugated to a lipophilic substituent. In yet other embodiments, three or even more amino acid side chains are each conjugated to a lipophilic substituent. When a compound comprises two or more lipophilic substituents, they may be identical or different substituents.

[0344] In certain embodiments, only one lipophilic group Φ is present in the molecule.

[0345] The term "conjugated" is used herein to describe the covalent attachment of one identifiable chemical moiety to another identifiable chemical moiety, as well as the structural relationship between such moieties. It should not be considered to imply any particular method of synthesis. One or more spacers Z 2 (when present) is used in compounds with lipophilic substituent Z 1 Provide a space between.

[0346] The lipophilic substituent may be linked to the N-terminal nitrogen or to the amino acid side chain or to the spacer via an ester, sulfonyl ester, thioester, amide or sulfonamide. Thus, it will be appreciated that the lipophilic substituent may comprise an acyl group, a sulfonyl group, an N atom, an O atom or an S atom forming part of the ester, sulfonyl ester, thioester, amide or sulfonamide.

[0347] The acyl group in the lipophilic substituent forms part of an amide or ester with the N-terminal nitrogen or an amino acid side chain or a spacer. The lipophilic substituent may comprise a hydrocarbon chain having 10 to 24 carbon (C) atoms (e.g., 10 to 22 C atoms, e.g., 10 to 20 C atoms). Preferably, it has at least 11 carbon atoms, and preferably it has 18 C atoms or less. For example, the hydrocarbon chain may comprise 12, 13, 14, 15, 16, 17 or 18 carbon atoms. The hydrocarbon chain may be straight or branched, and may be saturated or unsaturated.

[0348] The hydrocarbon chain may incorporate a phenylene or piperazinyl moiety throughout its length, for example, as shown below (wherein - indicates a point of attachment within the chain). These groups should be "counted" as 4 carbon atoms in the chain length.

[0349]

[0350] From the above discussion, it will be understood that the hydrocarbon chain may be substituted with a moiety that forms part of the connection to the amino acid side chain or spacer, such as an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. Most preferably, the hydrocarbon chain is substituted with an acyl group, and thus the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl or eicosanoyl. Alternatively, Z 1 The group is derived from the formula HOOC–(CH2) 12-22 The long-chain saturated α,ω-dicarboxylic acid of -COOH is preferably selected from long-chain saturated α,ω-dicarboxylic acids having an even number of carbon atoms in the aliphatic chain.

[0351] In other words, Z 1 Can be A–C 12-22 Alkylene -(CO)-, wherein A is H or -COOH, and wherein the alkylene may be straight or branched, and may be saturated or unsaturated, and may optionally incorporate phenylene or piperazinyl moieties along its length.

[0352] For example, Z 1 It can be:

[0353] Dodecanoyl, i.e. H–(CH2) 11 –(CO)–;

[0354] Tetradecanoyl, i.e. H–(CH2) 13 –(CO)–;

[0355] Hexadecanoyl, i.e. H-(CH2) 15 -(CO)-;

[0356] 13-Carboxytridecanoyl, HOOC–(CH2) 12 –(CO)–;

[0357] 15-Carboxypentadecanoyl, HOOC–(CH2) 14 –(CO)–;

[0358] 17-Carboxyheptadecanoyl, HOOC–(CH2) 16 –(CO)–;

[0359] 19-Carboxynonadecanoyl, HOOC–(CH2) 18 –(CO)–; or

[0360] 21-Carboxyheneicosanoyl, HOOC–(CH2) 20 –(CO)–.

[0361] The carboxylic acid, if present, may be replaced by a bioisomer, a phosphate or a sulfonate. Suitable bioisomers of carboxylic acids are known in the art and include tetrazoles, acylsulfonimides, acylhydroxylamines and squaric acid derivatives.

[0362] As mentioned above, the lipophilic substituent Z 1 One or more spacers Z 2 Conjugated to amino acid side chains or the N-terminal nitrogen.

[0363] When present, the spacer is linked to the lipophilic substituent and to the amino acid side chain or the N-terminal nitrogen. The spacer may be independently linked to the lipophilic substituent and the amino acid side chain via an ester, sulfonyl ester, thioester, amide or sulfonamide. Thus, it may comprise two moieties independently selected from: an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. The spacer may consist of a straight chain C 1-10 A hydrocarbon chain or more preferably a straight chain C 1-5 In addition, the spacer region may be substituted with one or more substituents selected from the following: 1-6 Alkyl, C 1-6 Alkylamine, C 1-6 Alkyl hydroxyl and C 1-6 Alkyl carboxyl.

[0364] The spacer can be, for example, the residue of any naturally occurring or non-natural amino acid. For example, the spacer can be the residues of Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, Glu, Asp, γ-Glu, β-Asp, ε-Lys, Asp, Ser, Thr, Dapa, Gaba, Aib, β-Ala (i.e., 3-aminopropionyl), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 8-amino-3,6-dioxaoctanoyl. In certain embodiments, the spacer is Glu, γ-Glu, ε-Lys, β-Ala (i.e., 3-aminopropionyl), 4-aminobutyryl, 8-aminooctanoyl or 8-amino-3,6-dioxaoctanoyl (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazine-1-yl)-carboxylic acid. In the present invention, γGlu and isoGlu can be used interchangeably.

[0365] Z 2Suitably, it is a sequence of 1 to 6 compound residues selected from the group consisting of γGlu, βAsp, D, E, K, Orn, S, T, A, βAla, G, P, V, L, I, Y, Q, N, Dapa, Gaba or Aib, or the corresponding D forms thereof, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl and 10-aminodecanoyl, 8-amino-3,6-dioxaoctanoic acid (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazin-1-yl)-carboxylic acid.

[0366] For example, Z 2 May be or include:

[0367] [γGlu];

[0368] [γGlu][Peg3][Peg3]-;

[0369] [(Piperazin-1-yl)-acetyl][Peg3][Peg3];

[0370] [γGlu]-G-[γGlu];

[0371] [γGlu]-K-[γGlu];

[0372] [γGlu]-KG-[γGlu]; or

[0373] [γGlu]-G-[Peg3][γGlu][Peg3].

[0374] Z 2 The bond is suitably via an amide bond on each side. Other suitable bonds may be used with commensurate atom replacement; for example, sulfenamide, sulfonamide or ester bonds or amino, ether, or thioether bonds are contemplated.

[0375] In other words, in some aspects, the lipophilic group Φ is Z 1 - or Z 1 -Z 2 -;in

[0376] Z 1 A–C 12-22 Alkylene –(CO)–;

[0377] wherein A is H or -COOH, and wherein the alkylene group may be linear or branched, and may be saturated or unsaturated, and may optionally incorporate phenylene or piperazinylene moieties in its length; and

[0378] Z 2is a sequence of 1 to 6 compound residues selected from the group consisting of γ-Glu, βAsp, D, E, K, Orn, S, T, A, β-Ala, G, P, V, L, I, Y, Q, N, Dapa, Gaba or Aib or their corresponding D forms, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl and 10-aminodecanoyl, 8-amino-3,6-dioxaoctanoic acid (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazin-1-yl)-carboxylic acid, such as a linker selected from the group consisting of:

[0379] [Glu],

[0380] [γGlu][Peg3][Peg3]-;

[0381] [(Piperazin-1-yl)-acetyl][Peg3][Peg3];

[0382] [γGlu]-G-[γGlu];

[0383] [γGlu]-K-[γGlu];

[0384] [γGlu]-KG-[γGlu]; and

[0385] [γGlu]-G-[Peg3][γGlu][Peg3].

[0386] The amino acid side chain conjugated to the lipophilic substituent generally comprises a carboxyl, hydroxyl, thiol, amide or amine group to form an ester, sulfonyl ester, thioester, amide or sulfonamide with the spacer or lipophilic substituent. An amide bond may be particularly preferred, and thus the amino acid may be any amino acid having an amine group in its side chain, although side chains with other functional groups are obviously contemplated. Thus, the amino acid side chain may be a side chain of a Glu, Lys, Ser, Cys, Dbu, Dpr or Orn residue. For example, it may be a side chain of a Lys, Glu or Cys residue. When two or more side chains carry a lipophilic substituent, they may be independently selected from those residues.

[0387] Typically, the amino acid side chain is that of a Lys residue.

[0388] The following formula shows a lipophilic moiety Z 1 and spacer Z 2 An example of a lipophilic substituent:

[0389]

[0390] Here, the side chain of the Lys residue is linked to the γGlu spacer (Z2 ) is covalently linked. 1 ) is covalently linked to the γGlu spacer via an amide bond. This combination of a spacer conjugated to a Lys residue and a lipophilic moiety can be represented by the shorthand notation K (hexadecanoyl-γGlu), for example when shown in the formula of a particular compound. γGlu may also be referred to as isoGlu, and hexadecanoyl may also be referred to as palmitoyl. Therefore, it is apparent that the notation (hexadecanoyl-γGlu) is equivalent to the notation (isoGlu (Palm)) or (isoGlu (palmitoyl)) used, for example, in PCT / GB2008 / 004121.

[0391] Alternative Z 1 The group is derived from the formula HOOC-(CH2) shown below 12-22 -COOH long-chain saturated α,ω-dicarboxylic acids,

[0392]

[0393] Here, the side chain of the Lys residue is linked to the γGlu spacer (Z 2 ) is covalently linked. 15-Carboxypentadecanoyl (Z 1 ) is covalently linked to the γGlu spacer via an amide bond. This combination of a spacer and a lipophilic moiety conjugated to a Lys residue can be represented by the shorthand notation K (15-carboxypentadecanoyl-γ-Glu), for example when shown in the formula of a particular compound. γGlu may also be referred to as isoGlu.

[0394] Certain preferred Φ groups (Z 1 - and Z 1 -Z 2 -)include:

[0395] [15-carboxy-pentadecanoyl];

[0396] [15-carboxy-pentadecanoyl][γGlu],

[0397] [15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3];

[0398] [19-carboxy-nonadecanoyl][γGlu][Peg3][Peg3];

[0399] [15-Carboxy-pentadecanoyl][(piperazin-1-yl)-acetyl][Peg3][Peg3];

[0400] [17-carboxy-heptadecanoyl][γGlu]G[γGlu];

[0401] [17-carboxy-heptadecanoyl][γGlu]K[γGlu];

[0402] [17-carboxy-heptadecanoyl][γGlu]KG[γGlu];

[0403] [17-carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu][Peg3];

[0404] [15-carboxy-pentadecanoyl][γGlu]G[γGlu];

[0405] [17-carboxy-heptadecanoyl];

[0406] [17-Carboxy-heptadecanoyl][γGlu]

[0407] [19-carboxy-nonadecanoyl][γGlu]G[γGlu]; and

[0408] [17-Carboxy-heptadecanoyl][γGlu][Peg3][Peg3].

[0409] Φ group (Z 1 - and Z 1 -Z 2 -) are shown below, where the wavy line indicates attachment to the peptide (to an amino acid side chain, the N-terminal nitrogen, or the C-terminal carbon):

[0410] [19-Carboxy-nonadecanoyl][γGlu]G[γGlu]:

[0411]

[0412] [17-Carboxy-heptadecanoyl][γGlu]G[γGlu]:

[0413]

[0414] [15-Carboxy-pentadecanoyl]-:

[0415]

[0416] [17-Carboxy-heptadecanoyl]-:

[0417]

[0418] [(15-Carboxy-pentadecanoyl)-[(piperazin-1-yl)-acetyl][Peg3][Peg3]:

[0419]

[0420] [17-Carboxy-heptadecanoyl][γGlu]:

[0421]

[0422] [17-Carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu][Peg3]:

[0423]

[0424] [17-Carboxy-heptadecanoyl][γGlu]KG[γGlu]:

[0425]

[0426] [17-Carboxy-heptadecanoyl][γGlu]K[γGlu]:

[0427]

[0428] [17-Carboxy-heptadecanoyl][γGlu][Peg3][Peg3]:

[0429]

[0430] The skilled person will be familiar with suitable techniques for preparing the compounds used in the context of the present invention. Some examples of suitable chemical processes are described in WO98 / 08871, WO00 / 55184, WO00 / 55119, Madsen et al., J. Med. Chem. 50:6126-32 (2007), and Knudsen et al., J. Med Chem. 43:1664-1669 (2000), which are incorporated herein by reference.

[0431] In some embodiments, a compstatin analog has a lipophilic group Φ as described above conjugated to an amino acid at one or more positions corresponding to positions 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 13 (i.e., positions X1 to X13) of a compstatin-like sequence.

[0432] In some embodiments, a compstatin analog has a lipophilic substituent as described above conjugated to an amino acid at one or more of the positions corresponding to positions X1, X11, or X13, or to an amino acid within R1 or R2 or at the N-terminus (eg, group Y1).

[0433] For C-terminal acylation or lipidation of peptides, well-established conjugation strategies have been developed. For example, such conjugation can be performed by click chemistry (i.e., a diorthogonal azide-alkyne conjugation reaction catalyzed by Cu(I)) or by other conjugation strategies known to those skilled in the art of peptide chemistry.

[0434] A compstatin analog may comprise one of the following sequences:

[0435] IC(1)IWQDWGAHRC(1)T

[0436] IC(1)IWQDWGEHRC(1)T

[0437] ESSAIC(1)IWQDWGEHRC(1)T

[0438] IC(1)I[1MeTrp]QDWGEHRC(1)T

[0439] IC(1)IWQDWGKHRC(1)T

[0440] IC(1)IWQDWGSHRC(1)T

[0441] IC(1)IWQKWGEHRC(1)T

[0442] IC(1)IWQKWGAHRC(1)TGAES

[0443] YC(1)IWQDWGEHRC(1)T

[0444] ESSAYC(1)IWQDWGEHRC(1)T

[0445] [Sar]C(1)IWQDWGEHRC(1)T

[0446] IC(1)IWQDWGAHRC(1)E

[0447] IC(1)IWQDWGEHRC(1)[Sar]

[0448] ESSAIC(1)IWQDWGEHRC(1)TGAES

[0449] IC(1)IWQDWGEHRC(1)TGAES

[0450] IC(1)IWQEWGEHRC(1)T

[0451] IC(1)IWQDWGDHRC(1)T

[0452] IC(1)IWQDWGRHRC(1)T

[0453] IC(1)IWQDWGAHSC(1)T

[0454] IC(1)IWQDWGEHSC(1)T

[0455] IC(1)IWQDWGEHRC(1)S

[0456] IC(1)IWQDWGEHRC(1)E

[0457] FC(1)IWQDWGEHRC(1)T

[0458] AGAINST IC(1)IWQDWGEHRC(1)

[0459] IC(1)IWQDWGEHRC(1)TEA

[0460] IC(1)IWQDWGEHRC(1)TE

[0461] IC(1)IWQDWGEHRC(1)EGE

[0462] EGSAIC(1)IWQDWGEHRC(1)[Sar]E

[0463] EGSAIC(1)IWQDWGEHRC(1)T

[0464] EGEIC(1)IWQDWGEHRC(1)T

[0465] ESEIC(1)IWQDWGEHRC(1)T

[0466] SEIC(1)IWQDWGEHRC(1)TEA

[0467] EIC(1)IWQDWGEHRC(1)TE

[0468] AGAINST EIC(1)IWQDWGEHRC(1)

[0469] EGEIC(1)IWQDWGEHRC(1)EGE

[0470] ESEIC(1)IWQDWGEHRC(1)EGE

[0471] KEKIC(1)IWQDWGEHRC(1)GOAT

[0472] EKGIC(1)IWQDWGEHRC(1)TEKP

[0473] IC(1)IWQDWGEHRC(1)TEGK

[0474] GSAIC(1)IWQDWGEHRC(1)[Sar]E

[0475] SAIC(1)IWQDWGEHRC(1)[Sar]E

[0476] SAIC(1)IWQDWGEHRC(1)TEG

[0477] FC(1)IWQDWGEHRC(1)TGAE

[0478] EGSAIC(1)IWQDWGEHRC(1)[Sar]EGE

[0479] EGSAFC(1)IWQDWGEHRC(1)[Sar]E

[0480] ESSAIC(1)IWQDWGAHRC(1)T

[0481] IC(1)IWQDWGAHRC(1)TGAES

[0482] {d}YIC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)-[N-Me-Ile]

[0483] EGSAIC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E

[0484] EGSAIC(1)I[2-Nal]QDWGEHRC(1)[Sar]E

[0485] IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES

[0486] IC(1)I[2-Nal]QDWGEHRC(1)TGAES

[0487] EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E

[0488] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E

[0489] EGSAIC(1)IWQDWGEHRC(1)TE

[0490] EGSAFC(1)I[1-Nal]QDWGEHRC(1)TE

[0491] EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)TE

[0492] EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE

[0493] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)TE

[0494] EGSAFC(1)I[2-Nal]QDWGEHRC(1)TE

[0495] FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES

[0496] YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES

[0497] FC(1)I[1-Nal]QDWGEHRC(1)TGAES

[0498] FC(1)I[2-Nal]QDWGEHRC(1)TGAES

[0499] YC(1)I[2-Nal]QDWGEHRC(1)TGAES

[0500] YC(1)IWQDWGEHRC(1)TGAES

[0501] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES

[0502] YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS

[0503] YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA

[0504] EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E

[0505] SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA

[0506] FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES

[0507] {d}YFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES

[0508] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES

[0509] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA

[0510] SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]EA

[0511] SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TEA

[0512] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E

[0513] SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E

[0514] EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA

[0515] SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA

[0516] SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA

[0517] SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA

[0518] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)SEA

[0519] EFC(1)I[1-Me-Trp]QDWGEHRC(1)ES

[0520] SEFC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]EA

[0521] GEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA

[0522] GE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA

[0523] SE[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)TEA

[0524] SE[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA

[0525] {d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA

[0526] For example, a compstatin analog can be:

[0527] Ac-IC(1)IWQDWGAHRC(1)T-NH2(Compound 1)

[0528] Ac-IC(1)IWQDWGEHRC(1)T-NH2(Compound 2)

[0529] Ac-ESSAIC(1)IWQDWGEHRC(1)T-NH2(Compound 3)

[0530] Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)T-NH2(Compound 4)

[0531] Ac-IC(1)IWQDWGKHRC(1)T-NH2(Compound 5)

[0532] Ac-IC(1)IWQDWGSHRC(1)T-NH2(Compound 6)

[0533] Ac-IC(1)IWQKWGEHRC(1)T-NH2(Compound 7)

[0534] Ac-IC(1)IWQKWGAHRC(1)TGAES-NH2(Compound 8)

[0535] Ac-YC(1)IWQDWGEHRC(1)T-NH2(Compound 9)

[0536] Ac-ESSAYC(1)IWQDWGEHRC(1)T-NH2(Compound 10)

[0537] Ac-[Sar]C(1)IWQDWGEHRC(1)T-NH2(Compound 11)

[0538] Ac-IC(1)IWQDWGAHRC(1)E-NH2(Compound 12)

[0539] Ac-IC(1)IWQDWGEHRC(1)[Sar]-NH2(Compound 13)

[0540] Ac-ESSAIC(1)IWQDWGEHRC(1)TGAES-NH2(Compound 14)

[0541] Ac-IC(1)IWQDWGEHRC(1)TGAES-NH2(Compound 15)

[0542] Ac-IC(1)IWQEWGEHRC(1)T-NH2(Compound 16)

[0543] Ac-IC(1)IWQDWGDHRC(1)T-NH2(Compound 17)

[0544] Ac-IC(1)IWQDWGRHRC(1)T-NH2(Compound 18)

[0545] Ac-IC(1)IWQDWGAHSC(1)T-NH2(Compound 19)

[0546] Ac-IC(1)IWQDWGEHSC(1)T-NH2(Compound 20)

[0547] Ac-IC(1)IWQDWGEHRC(1)S-NH2(Compound 21)

[0548] Ac-IC(1)IWQDWGEHRC(1)E-NH2(Compound 22)

[0549] Ac-FC(1)IWQDWGEHRC(1)T-NH2(Compound 23)

[0550] Ac-IC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 24)

[0551] Ac-IC(1)IWQDWGEHRC(1)TEA-NH2(Compound 25)

[0552] Ac-IC(1)IWQDWGEHRC(1)TE-NH2(Compound 26)

[0553] Ac-IC(1)IWQDWGEHRC(1)EGE-NH2(Compound 27)

[0554] Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 28)

[0555] Ac-EGSAIC(1)IWQDWGEHRC(1)T-NH2(Compound 29)

[0556] Ac-EGEIC(1)IWQDWGEHRC(1)T-NH2(Compound 30)

[0557] Ac-ESEIC(1)IWQDWGEHRC(1)T-NH2(Compound 31)

[0558] Ac-SEIC(1)IWQDWGEHRC(1)TEA-NH2(Compound 32)

[0559] Ac-EIC(1)IWQDWGEHRC(1)TE-NH2(Compound 33)

[0560] Ac-EIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 34)

[0561] Ac-EGEIC(1)IWQDWGEHRC(1)EGE-NH2(Compound 35)

[0562] Ac-ESEIC(1)IWQDWGEHRC(1)EGE-NH2(Compound 36)

[0563] Ac-KEKIC(1)IWQDWGEHRC(1)TEKE-NH2(Compound 37)

[0564] Ac-EKGIC(1)IWQDWGEHRC(1)TEKP-NH2(Compound 38)

[0565] Ac-IC(1)IWQDWGEHRC(1)TEGK-NH2(Compound 39)

[0566] Ac-GSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 40)

[0567] Ac-SAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 41)

[0568] Ac-SAIC(1)IWQDWGEHRC(1)TEG-NH2(Compound 42)

[0569] Ac-FC(1)IWQDWGEHRC(1)TGAE-NH2(Compound 43)

[0570] Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]EGE-NH2(Compound 44)

[0571] Ac-EGSAFC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 45)

[0572] Ac-ESSAIC(1)IWQDWGAHRC(1)T-NH2(Compound 46)

[0573] Ac-IC(1)IWQDWGAHRC(1)TGAES-NH2(Compound 47)

[0574] H-{d}YIC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)[N-Me-Ile]-NH2 (Compound 48)

[0575] Ac-EGSAIC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2(Compound 49)

[0576] Ac-EGSAIC(1)I[2-Nal]QDWGEHRC(1)[Sar]E-NH2(Compound 50)

[0577] Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2(Compound 51)

[0578] Ac-IC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2(Compound 52)

[0579] Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2(Compound 53)

[0580] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 54)

[0581] Ac-EGSAIC(1)IWQDWGEHRC(1)TE-NH2(Compound 55)

[0582] Ac-EGSAFC(1)I[1-Nal]QDWGEHRC(1)TE-NH2(Compound 56)

[0583] Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 57)

[0584] Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-NH2 (Compound 58)

[0585] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 59)

[0586] Ac-EGSAFC(1)I[2-Nal]QDWGEHRC(1)TE-NH2 (Compound 60)

[0587] Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 61)

[0588] Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 62)

[0589] Ac-FC(1)I[1-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 63)

[0590] Ac-FC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 64)

[0591] Ac-YC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 65)

[0592] Ac-YC(1)IWQDWGEHRC(1)TGAES-NH2 (Compound 66)

[0593] AcSEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 67)

[0594] Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS-NH2 (Compound 68)

[0595] Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA-NH2 (Compound 69)

[0596] Ac-EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E-NH2 (Compound 70)

[0597] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 71)

[0598] Ac-FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 72)

[0599] H-{d}YFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 73)

[0600] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES-NH2 (Compound 74)

[0601] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 75)

[0602] Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]EA-NH2 (Compound 76)

[0603] Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TEA-NH2 (Compound 77)

[0604] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 78)

[0605] Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E-NH2 (Compound 79)

[0606] Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 80)

[0607] Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 81)

[0608] Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 82)

[0609] Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 83)

[0610] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)SEA-NH2 (Compound 84)

[0611] Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)ES-NH2 (Compound 85)

[0612] Ac-SEFC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]EA-NH2 (Compound 86)

[0613] Ac-GEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 87)

[0614] Ac-GE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 88)

[0615] Ac-SE[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)TEA-NH2(Compound 89)

[0616] Ac-SE[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 90)

[0617] H-{d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 91)

[0618] Alternatively, the compstatin analog may comprise one of the following sequences:

[0619] [K ＊ ]GSAIC(1)IWQDWGEHRC(1)TEGE(Compound 100)

[0620] ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊ ](Compound 113)

[0621] EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-[K ＊ ](Compound 134)

[0622] EGSAIC(1)IWQDWGEHRC(1)TEG[K ＊ ](Compound 101)

[0623] EGSAYC(1)I[1-Me-Trp]QDWGEH[K ＊ ]C(1)[Sar]E (Compound 103)

[0624] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-[K ＊ ](Compound 104)

[0625] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊](Compound 109)

[0626] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-[K ＊ ](Compound 110)

[0627] EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]-[K ＊ ](Compound 111)

[0628] FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K ＊ ](Compound 102)

[0629] IC(1)IWQDWGEHRC(1)TEG-[K ＊ ](Compound 92)

[0630] IC(1)IWQDWGEHRC(1)TEGE-[K ＊ ](Compound 94)

[0631] SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-[K ＊ ](Compound 105)

[0632] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K ＊ ](Compound 119)

[0633] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ ](Compound 123)

[0634] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-[K ＊ ](Compound 129)

[0635] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-[K ＊ ](Compound 138)

[0636] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-[K ＊ ](Compound 140)

[0637] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ ](Compound 127)

[0638] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-[K ＊ ](Compound 139)

[0639] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-[K ＊ ](Compound 132)

[0640] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-[K ＊ ](Compound 136)

[0641] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]E-[K ＊ ](Compound 137)

[0642] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-[K ＊ ](Compound 130)

[0643] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-[K ＊ ](Compound 142)

[0644] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-[K ＊ ](Compound 126)

[0645] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-[K ＊ ](Compound 133)

[0646] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K ＊ ](Compound 135)

[0647] SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K ＊ ](Compound 120)

[0648] SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ (Compound 124)

[0649] SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K ＊ (Compound 112)

[0650] SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ (Compound 117)

[0651] SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊ (Compound 114)

[0652] SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]A-[K ＊ (Compound 121)

[0653] SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K ＊ (Compound 122)

[0654] SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ (Compound 125)

[0655] EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E(Compound 107)

[0656] ESSAIC(1)IWQDWGEHRC(1)TEGE(Compound 99)

[0657] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3][Peg3]-[K ＊ (Compound 143)

[0658] SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-[K ＊ (Compound 144)

[0659] EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-[K ＊ ](Compound 145)

[0660] For example, a compstatin analog may comprise one of the following sequences:

[0661] Ac-[K ＊ ]GSAIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 100)

[0662] Ac-ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊ ]-NH2 (Compound 113)

[0663] Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-[K ＊ ]-NH2 (Compound 134)

[0664] Ac-EGSAIC(1)IWQDWGEHRC(1)TEG-[K ＊ ]-NH2(Compound 101)

[0665] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEH[K ＊ ]C(1)[Sar]E-NH2 (Compound 103)

[0666] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-[K ＊ ]-NH2 (Compound 104)

[0667] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊ ]-NH2 (Compound 109)

[0668] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-[K ＊ ]-NH2 (Compound 110)

[0669] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]-[K ＊ ]-NH2 (Compound 111)

[0670] Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K ＊ ]-NH2 (Compound 102)

[0671] Ac-IC(1)IWQDWGEHRC(1)TEG-[K ＊ ]-NH2 (Compounds 92, 93, 95, 96, 98)

[0672] Ac-IC(1)IWQDWGEHRC(1)TEGE-[K ＊ ]-NH2 (Compound 94, 97)

[0673] Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-[K ＊ ]-NH2 (Compound 105, 106)

[0674] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K ＊ ]-NH2 (Compound 119)

[0675] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ ]-NH2 (Compound 123)

[0676] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-[K ＊ ]-NH2 (Compound 129)

[0677] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-[K ＊ ]-NH2 (Compound 138)

[0678] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-[K ＊ ]-NH2 (Compound 140)

[0679] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ ]-NH2 (Compounds 127, 128)

[0680] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-[K ＊ ]-NH2 (Compound 139, 141)

[0681] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-[K ＊ ]-NH2 (Compound 132)

[0682] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-[K ＊ ]-NH2 (Compound 136)

[0683] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]E-[K ＊ ]-NH2 (Compound 137)

[0684] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-[K ＊ ]-NH2 (Compound 130, 131)

[0685] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE-[Peg3]ES-[K ＊ ]-NH2 (Compound 142)

[0686] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE-[Peg3][Peg3]-[K ＊ ]-NH2 (Compound 126)

[0687] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-[K ＊ ]-NH2 (Compound 133)

[0688] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K ＊ ]-NH2 (Compound 135)

[0689] Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K ＊ ]-NH2 (Compound 120)

[0690] Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ -NH2 (Compound 124)

[0691] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K ＊ -NH2 (Compounds 112, 118)

[0692] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ -NH2 (Compound 117)

[0693] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K ＊ -NH2 (Compounds 114, 115, 116)

[0694] Ac-SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]A-[K ＊ -NH2 (Compound 121)

[0695] Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K ＊ -NH2 (Compound 122)

[0696] Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K ＊ -NH2 (Compound 125)

[0697] Φ-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compounds 107, 108)

[0698] Φ-ESSAIC(1)IWQDWGEHRC(1)TEGE-NH2 (Compound 99)

[0699] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3][Peg3]-[K ＊ -NH2 (Compound 143)

[0700] Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-[K ＊ ]-NH2 (Compound 144)

[0701] Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-[K ＊ ]-NH2 (Compound 145)

[0702] For example, a compstatin analog can be:

[0703] Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH2(Compound 92)

[0704] Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 93)

[0705] Ac-IC(1)IWQDWGEHRC(1)TEGE-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 94)

[0706] Ac-IC(1)IWQDWGEHRC(1)TEG-K((15-carboxy-pentadecanoyl)-[(piperazin-1-yl)-acetyl][Peg3][Peg3])-NH2(Compound 95)

[0707] Ac-IC(1)IWQDWGEHRC(1)TEG-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 96)

[0708] Ac-IC(1)IWQDWGEHRC(1)TEGE-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 97)

[0709] Ac-IC(1)IWQDWGEHRC(1)TEG-K([19-carboxy-nonadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 98)

[0710] [15-Carboxy-pentadecanoyl]-ESSAIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 99)

[0711] Ac-[K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])]-GSAIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 100)

[0712] Ac-EGSAIC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH2(Compound 101)

[0713] Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2 (Compound 102)

[0714] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEH-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-C(1)[Sar]E-NH2 (Compound 103)

[0715] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2 (Compound 104)

[0716] Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([17-carboxy-heptadecanoyl][γGlu]KG[γGlu])-NH2 (Compound 105)

[0717] Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 106)

[0718] [15-Carboxy-pentadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 107)

[0719] [17-Carboxy-heptadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 108)

[0720] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 109)

[0721] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 110)

[0722] Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([γGlu]-K([17-carboxy-heptadecanoyl][γGlu](peg3)(peg3))-NH2(Compound 111)

[0723] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 112)

[0724] Ac-ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 113)

[0725] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 114)

[0726] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 115)

[0727] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-K[γGlu])-NH2 (Compound 116)

[0728] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 117)

[0729] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH2 (Compound 118)

[0730] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl-][γGlu]G[Peg3][γGlu][Peg3])-NH2(Compound 119)

[0731] Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH2(Compound 120)

[0732] Ac-SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]AK([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH2 (Compound 121)

[0733] Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH2 (Compound 122)

[0734] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 123)

[0735] Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3[Peg3]-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 124)

[0736] Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 125)

[0737] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl)[γGlu]G[γGlu]])-NH2(Compound 126)

[0738] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]-EGE-[Peg3][Peg3]-K([15-carboxy-pentadecanoyl][γGlu]G[γGlu])-NH2(Compound 127)

[0739] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([19-carboxy-nonadecanoyl][γGlu]G[γGlu])-NH2(Compound 128)

[0740] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 129)

[0741] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 130)

[0742] Ac-SEFC(1)I[1-Me-Trp]-QDWGEHRC(1)TEGEGGG-K([15-carboxy-pentadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 131)

[0743] Ac-SEFC(1)I[1-Me-Trp]-QDWGEHRC(1)[Sar]EK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 132)

[0744] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2(Compound 133)

[0745] Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 134)

[0746] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-hexadecanoyl][γGlu]G[γGlu])-NH2(Compound 135)

[0747] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2(Compound 136)

[0748] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]EK([17-carboxy-heptadecanoyl][γGlu]G[γGlu]])-NH2(Compound 137)

[0749] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 138)

[0750] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 139)

[0751] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 140)

[0752] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl][γGlu])-NH2(Compound 141)

[0753] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu])-NH2(Compound 142)

[0754] Ac-SEFC(1)I[1-Me-Trp]QDWGEHR[C(1)[Sar]EGE[Peg3][Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 143)

[0755] Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 144)

[0756] Ac-EF[C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 145).

[0757] Compstatin analogs prepared in the prior art have been shown to have improved activity compared to the parent peptide, i.e., up to about 99-fold (Mallik, B. et al., 2005, supra; WO 2004 / 026328), and up to about 264-fold (Katragadda et al., 2006, supra; WO 2007 / 062249).

[0758] According to the present invention, information on the biological and physicochemical properties of Ac-comstatin binding to C3 has been used to design compstatin analogs with significantly improved activity compared to the parent compstatin analog.

[0759] Preferably, a compstatin analog has greater activity than Ac-comstatin, e.g., at least 10-fold greater activity, at least 20-fold greater activity, at least 30-fold greater activity than Ac-comstatin. In other embodiments, an analog has at least 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, or more activity than Ac-comstatin, as compared using an assay described in the Examples.

[0760] Compounds of the invention are generally more active than an otherwise identical compound having a valine instead of an isoleucine at the position corresponding to Val3 of compstatin.

[0761] Compstatin analogs can bind to C3 and / or C3b and can inhibit activation of the complement cascade, particularly downstream of C3, such as by inhibiting cleavage of C3 by C3 convertase.

[0762] Compstatin analogs are also generally capable of inhibiting complement-driven hemolysis. Complement-driven hemolysis is generally assessed by contacting serum (e.g., human serum) from a first mammalian species with red blood cells (erythrocytes; RBCs) from a second mammalian species (e.g., sheep or any other suitable species), typically in the presence of a mammalian immunoglobulin that is capable of binding to the erythrocytes (in a "hemolysis assay"). Complement in the serum is activated by the cell-bound immunoglobulin, resulting in the lysis of the erythrocytes, i.e., hemolysis. The immunoglobulin may be from the first species, or may be from a third mammalian species, as long as it is capable of activating complement from the first species.

[0763] In such an assay, the test compound is usually pre-incubated with the serum before contacting the serum with the erythrocytes. The erythrocytes may also be pre-incubated with immunoglobulins before contacting with the serum.

[0764] In the following examples, human serum was preincubated with the test compound and sheep erythrocytes were preincubated with rabbit antiserum raised against sheep erythrocytes prior to combining the serum and erythrocytes.

[0765] Thus, the activity of a compstatin analog can be determined with reference to one or more biological activities selected from the group consisting of: (1) binding to C3 protein, (2) binding to C3b protein, (3) inhibiting cleavage of native C3 by C3 convertase, and (4) inhibiting activation of the complement system.

[0766] Thus, compstatin analogs of the invention can bind C3 or C3b with a higher affinity than compstatin. For example, their Kd can be at least 10-fold lower, at least 20-fold lower, or at least 30-fold lower than Ac-comstatin, e.g., at least 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold lower than Ac-comstatin. Kd can be determined by surface plasmon resonance (SPR), e.g., using the assay described in Example 4.

[0767] A compstatin analog of the invention generally binds C3 or C3b with greater affinity (ie, lower Kd) than an otherwise identical compound having a valine rather than isoleucine at the position corresponding to Val3 of compstatin.

[0768] A compstatin analog of the invention has a greater ability to inhibit hemolysis than Ac-comstatin. For example, it can have an IC that is at least 10-fold, at least 20-fold, or at least 30-fold lower than Ac-comstatin, such as at least 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold lower than Ac-comstatin. 50 Inhibit hemolysis.

[0769] The compstatin analogs of the invention generally have a greater ability to inhibit hemolysis (i.e., a lower IC ) than an otherwise identical compound having a valine instead of an isoleucine at the position corresponding to Val3 of compstatin. 50 ).

[0770] Preferably, the in vitro effects of the compounds of the invention are assessed by measuring their inhibitory effects on the classical complement pathway in a hemolytic assay (eg using the assay described in Example 2).

[0771] Compstatin analogs with acylation may have lower absolute activity than otherwise identical compounds without acylation, but may have additional benefits, including prolonged half-life in vivo, which may offset any apparent reduction in absolute activity.

[0772] Synthesis of compstatin analogs

[0773] The compstatin analogs of the invention are preferably synthesized by solid-phase or liquid-phase peptide synthesis methods. In this context, reference may be made to WO 98 / 11125, and especially Fields, GB et al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (2nd ed.), and the Examples herein.

[0774] According to the invention, compstatin analogs of the invention can be synthesized or produced in a variety of ways, including, for example, methods comprising:

[0775] (a) synthesizing a compstatin analog by a solid phase or liquid phase peptide synthesis method and recovering the synthesized compstatin analog obtained thereby; or

[0776] (b) expressing the precursor peptide sequence from a nucleic acid construct encoding the precursor peptide, recovering the expression product, and modifying the precursor peptide to produce a compound of the present invention.

[0777] The precursor peptide may be modified by introducing one or more non-proteinogenic amino acids, such as Aib, Orn, Dap, 1-Me-Trp, 1-Nal, 2-Nal, Sar, Glu or Dab, or by introducing appropriate terminal groups Y1 and / or Y2.

[0778] The expression is usually carried out by a nucleic acid encoding the precursor peptide, and the expression can be carried out in a cell or a cell-free expression system comprising such nucleic acid.

[0779] Preferably, the analogs of the invention are synthesized by solid phase or liquid phase peptide synthesis. In this context, reference may be made to WO98 / 11125, and especially Fields, GB et al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (Second Edition), and the examples herein.

[0780] For recombinant expression, the nucleic acid fragment encoding the precursor peptide is usually inserted into a suitable vector to form a cloning or expression vector. Depending on the purpose and type of application, the vector can be in the form of a plasmid, phage, cosmid, minichromosome or virus, but naked DNA that is only transiently expressed in certain cells is also an important vector. Preferred cloning and expression vectors (plasmid vectors) are capable of autonomous replication, thereby enabling the production of high copy numbers for high-level expression or for high-level replication of subsequent cloning.

[0781] In general, the expression vector comprises the following features in the 5'→3' direction and operably connected: a promoter for driving the expression of the nucleic acid fragment, an optional nucleic acid sequence encoding a leader peptide that enables secretion (secretion into the extracellular phase or, when appropriate, into the periplasm), a nucleic acid fragment encoding a precursor peptide, and an optional nucleic acid sequence encoding a terminator. It may comprise additional features, such as a selection marker and an origin of replication. When using an expression vector to operate in a production strain or cell line, it is preferred that the vector be able to be integrated into the host cell genome. The technician is very familiar with suitable vectors and can design vectors according to their specific requirements.

[0782] The vector of the present invention is used to transform host cells to produce the precursor peptide. Such transformed cells can be cultured cells or cell lines used to amplify nucleic acid fragments and vectors and / or to recombinantly produce the precursor peptide.

[0783] Preferred transformed cells are microorganisms, such as bacteria (e.g., species of Escherichia (e.g., E. coli), Bacillus (e.g., Bacillus subtilis), Salmonella or Mycobacterium (preferably non-pathogenic, such as Mycobacterium bovis (M. bovis) BCG)), yeast (e.g., Saccharomyces cerevisiae and Pichia pastoris) and protozoa. Alternatively, the transformed cell may be derived from a multicellular organism, i.e., it may be a fungal cell, an insect cell, an algae cell, a plant cell or an animal cell (e.g., a mammalian cell). For the purpose of cloning and / or optimizing expression, it is preferred that the transformed cell is capable of replicating the nucleic acid fragment of the invention. Cells expressing the nucleic acid fragment can be used for small-scale or large-scale preparation of the peptides of the invention.

[0784] When the precursor peptide is produced by transformed cells, it is convenient, but far from essential, for the expression product to be secreted into the culture medium.

[0785] Medical conditions

[0786] In a broad aspect, the invention provides compstatin analogs of the invention for use as medicaments or for use in therapy.

[0787] The compstatin analogs described herein have biological activity that binds to the C3 protein and / or inhibits complement activation. In general, the compstatin analogs of the invention can be used to treat or prevent conditions associated with excessive or undesirable activation of the complement system. Complement can be activated via three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. The major activation event common to all three pathways is the proteolytic cleavage of the complement system central protein C3 by the C3 convertase into its activation products C3a and C3b. The generation of these fragments results in opsonization of pathogenic cells by C3b and iC3b, a process that renders pathogenic cells susceptible to phagocytosis or clearance and to activation of immune cells by interaction with complement receptors (Markiewski & Lambris, 2007, Am. J. Pathol., 171:715-727). Deposition of C3b on target cells also induces the formation of new convertase complexes and thus initiates a self-amplifying loop. The ensemble of plasma and cell surface binding proteins carefully regulates complement activation to prevent host cells from attacking themselves via the complement cascade. The 13 amino acid cyclic tridecapeptide used as a reference point for designing compstatin analogs of the invention inhibits complement activation by binding to C3 and / or C3b, thereby preventing cleavage of native C3 by the C3 convertase. Without wishing to be bound by any particular theory, the inventors believe that compstatin analogs of the invention also function in this manner and may share one or more biological activities selected from the group consisting of: (1) binding to C3 protein, (2) binding to C3b protein, (3) inhibiting cleavage of native C3 by the C3 convertase, and / or (4) inhibiting activation of the complement system. The biological activity of compstatin analogs of the invention can be determined in vitro by measuring their inhibitory effects on the classical complement pathway in a hemolytic assay, for example using the protocol set forth in the Examples below.

[0788] Excessive activation or inappropriate regulation of complement can lead to many pathological conditions, ranging from autoimmune diseases to inflammatory diseases (Holers, 2003, Clin. Immunol., 107: 140-51; Markiewski & Lambris, 2007, supra; Ricklin & Lambris, 2007, Nat. Biotechnol., 25: 1265-75; Sahu et al., 2000, J. Immunol., 165: 2491-9). These conditions include: (1) inhibition of complement activation to facilitate treatment of diseases or conditions including: age-related macular degeneration, Stargardt disease, periodontitis, diabetic retinopathy, glaucoma, uveitis, rheumatoid arthritis, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, cancer, and respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), allergic inflammation, emphysema, bronchitis, bronchiectasis, cystic fibrosis, tuberculosis, pneumonia, respiratory distress syndrome (RDS), and pulmonary edema. syndrome, RDS-neonatal and adult), rhinitis and sinusitis; bacterial infections, such as sepsis, ischemia-reperfusion injury in various tissues, myocardial infarction, anaphylaxis, paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, psoriasis, hidradenitis suppurativa, myasthenia gravis, systemic lupus erythematosus, CHAPLE syndrome, C3 glomerulopathy, IgA nephropathy, atypical hemolytic uremic syndrome, Crohn's disease, ulcerative colitis, antiphospholipid syndrome, or (2) inhibiting complement activation that occurs during cell or solid organ transplantation or when using artificial organs or implants (e.g., by coating or otherwise treating cells, organs, artificial organs or implants with the peptides of the invention); or (3) inhibiting complement activation that occurs during extracorporeal shunting of physiological fluids (blood, urine) (e.g., by coating tubing through which the fluid flows when shunted with a compstatin analog of the invention).

[0789] Pharmaceutical compositions and administration

[0790] In another aspect, the invention relates to a composition comprising a compstatin analog according to the invention, or a pharmaceutically acceptable salt or solvate thereof, and a carrier. In one embodiment of the invention, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition comprising a compstatin analog according to the invention, or a salt and / or solvate thereof, and a carrier, excipient, or vehicle. Thus, a compstatin analog, or a salt or solvate thereof (particularly a pharmaceutically acceptable salt and / or solvate thereof) according to the invention can be formulated into a composition or pharmaceutical composition prepared for storage or administration, and comprises a therapeutically effective amount of a compstatin analog, or a salt or solvate thereof according to the invention.

[0791] Suitable salts with bases include metal salts, for example alkali metal or alkaline earth metal salts.

[0792] In one embodiment, a pharmaceutical composition of the invention is one in which the compstatin analog is in the form of a pharmaceutically acceptable acid addition salt.

[0793] As will be apparent to one skilled in the medical arts, a "therapeutically effective amount" of a compstatin analog compound of the invention, or pharmaceutical composition thereof, will vary depending, among other things, on the age, weight, and / or sex of the subject (patient) being treated. Other factors that may be relevant include the physical characteristics of the specific patient under consideration, the patient's diet, the nature of any concomitant medications, the specific compound used, the specific mode of administration, the desired pharmacological effect, and the specific therapeutic indication. Because these factors and their relationship in determining such amounts are well known in the medical arts, it will be within the purview of the skilled artisan to determine a therapeutically effective dosage level, the amount necessary to achieve the desired result of treating and / or preventing and / or remedying the malabsorption and / or low-grade inflammation described herein, as well as other medical indications disclosed herein.

[0794] As used herein, the term "therapeutically effective amount" refers to an amount that reduces the symptoms of a given disorder or pathological condition, and which preferably normalizes physiological responses in an individual suffering from the disorder or pathological condition. Reduction of symptoms or normalization of physiological responses can be determined using methods routinely known in the art, and can vary with a given disorder or pathological condition. In one aspect, a therapeutically effective amount of one or more compstatin analogs or pharmaceutical compositions thereof is an amount that restores a measurable physiological parameter to substantially the same value (preferably within 30% of that value, more preferably within 20% of that value, and more preferably within 10% of that value) of the parameter in an individual not suffering from the disorder or pathological condition in question.

[0795] In one embodiment of the invention, administration of the compounds or pharmaceutical compositions of the invention is initiated at lower dosage levels and dosage levels are increased until the desired effect for prevention / treatment of the relevant medical indication is achieved. This will define a therapeutically effective amount. For a compstatin analog of the invention alone or as part of a pharmaceutical composition, such a human dosage of active compstatin analog can be about 0.01 pmol / kg to 500 μmol / kg body weight, about 0.01 pmol / kg to 300 μmol / kg body weight, 0.01 pmol / kg to 100 μmol / kg body weight, 0.1 pmol / kg to 50 μmol / kg body weight, 1 pmol / kg to 10 μmol / kg body weight, 5 pmol / kg to 5 μmol / kg body weight, 10 pmol / kg to 1 μmol / kg body weight, 50 pmol / kg to 0.1 μmol / kg body weight, 100 pmol / kg to 0.01 μmol / kg body weight, 0.001 μmol / kg to 0.5 μmol / kg body weight, 0.05 μmol / kg to 0.1 μmol / kg body weight.

[0796] The therapeutic dose and regimen most suitable for the treatment of a patient will of course vary with the disease or condition to be treated and according to the patient's weight and other parameters. Without wishing to be bound by any particular theory, it is expected that doses in the mg / kg range and shorter or longer treatment durations or frequencies may produce therapeutically useful results, such as statistically significant inhibition of the alternative or classical complement pathways. The dose size and dosing regimen most suitable for human use may be guided by the results obtained by the present invention and may be confirmed in appropriately designed clinical trials.

[0797] Effective dosages and treatment regimens can be determined by conventional means, starting with low doses in experimental animals and subsequently increasing the dose while monitoring the effects, and also systematically varying the dosage regimen. When determining the optimal dosage for a given subject, the clinician can consider many factors.

[0798] For local delivery to the eye, the pharmaceutical composition can be prepared in sterile saline or water with or without isotonicity, pH adjustment of preservatives such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutical composition can be formulated into an ointment such as petrolatum or eye drops (eyedrop). The method of topical application to the eye includes, for example, choroidal injection, injection through the sclera or placement of scleral patches, selective arterial catheterization, eye drops or eye ointments, and intraocular administration includes transretinal, subconjunctival bulbar, intravitreal injection, suprachoroidal injection, injection in the fascia sac (subtenon injection), scleral bag and sclerectomy injection, by osmotic pumps, etc. Alternatively, medicament can also be administered intravascularly, such as intravenous (IV) or intraarterial administration. In choroidal injection and scleral patches, clinicians use local methods to the eye after appropriate anesthesia (including analgesics and ophthalmoplegics) begins. A needle containing the therapeutic compound is injected into the choroid or sclera of the subject and inserted under sterile conditions. Once the needle is properly placed, the compound is injected into either or both of the choroid or sclera. When using any of these methods, the clinician can choose a sustained release or longer-acting formulation. Therefore, depending on the subject's tolerance to treatment and response, the process may be repeated only every few months or years.

[0799] The following examples are provided to describe the present invention in more detail. They are intended to illustrate rather than limit the present invention.

[0800] Example 1: Synthesis of Compstatin Analogs

[0801] General Peptide Synthesis

[0802]

[0803]

[0804] Instrumentation and synthetic strategy

[0805] The peptides were synthesized batchwise on a peptide synthesizer (e.g., CEM Liberty Peptide Synthesizer or Symphony X Synthesizer) according to a solid phase peptide synthesis procedure using 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and appropriate common protecting groups for peptide side chain functional groups.

[0806] As resins based on polymer supports, for example TentaGel TM The synthesizer was loaded with the resin swollen in DMF prior to use.

[0807] Coupling

[0808] CEM Liberty Peptide Synthesizer

[0809] The Fmoc protected amino acid solution (4 equivalents) was added to the resin along with the coupling reagent solution (4 equivalents) and the base solution (8 equivalents). The mixture was heated to 70 to 75° C. by a microwave unit and coupled for 5 minutes or for 60 minutes without heating. During the coupling, nitrogen was bubbled through the mixture.

[0810] Symphony X Synthesizer

[0811] The coupling solution was transferred to the reaction vessel in the following order: amino acid (4 eq.), HATU (4 eq.) and DIPEA (8 eq.). Unless otherwise stated, the coupling time was 10 min at room temperature (RT). The resin was washed with DMF (5 x 0.5 min). In case of repeated couplings, the coupling time was 45 min at room temperature in all cases.

[0812] Go to protection

[0813] CEM Liberty Peptide Synthesizer

[0814] The Fmoc group is deprotected using piperidine in DMF or other suitable solvent. The deprotection solution is added to the reaction vessel and the mixture is heated for 30 seconds to about 40°C. The reaction vessel is drained and fresh deprotection solution is added and then heated to 70 to 75°C for 3 minutes. After draining the reaction vessel, the resin is washed with DMF or other suitable solvent.

[0815] Symphony X Synthesizer

[0816] Fmoc deprotection was performed using 40% piperidine in DMF for 2.5 min and repeated using the same conditions. The resin was washed with DMF (5 x 0.5 min).

[0817] Side chain acylation

[0818] Fmoc-Lys(Dde)-OH or alternatively another amino acid with an orthogonal side chain protecting group is introduced at the acylation position (side chain lipidation). The N-terminus of the linear peptide is protected with Ac or Boc. While the peptide is still attached to the resin, the orthogonal side chain protecting groups are selectively cleaved using freshly prepared hydrazine hydrate (2% to 4%) in NMP for 2×15 minutes. The unprotected lysine side chain is then extended using standard coupling conditions and Fmoc deprotection with the desired building block. The lipidated portion is coupled as the last step.

[0819] Cutting

[0820] The dried peptide resin was treated with TFA and a suitable scavenger for about 2 hours. The volume of the filtrate was reduced and the crude peptide was precipitated after addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[0821] HPLC purification of crude peptide

[0822] The crude peptide was purified by preparative reverse phase HPLC: using a conventional HPLC instrument, such as a Gilson GX-281 equipped with a column (e.g., a 5×25 cm Gemini NX 5u C18 110A column) and a fraction collector with a 331 / 332 pump combination for binary gradient application, using a flow rate of 20 to 40 ml / min of an appropriate gradient of buffer A (0.1% formic acid, aq.) or A (0.1% TFA, aq.) and buffer B (0.1% formic acid, 90% MeCN, aq.) or B (0.1% TFA, 90% MeCN, aq.). The fractions were analyzed by analytical HPLC and MS, and the selected fractions were combined and lyophilized. The final product was characterized by HPLC and MS.

[0823] Oxidation

[0824] After purification and lyophilization of the crude linear peptide, the peptide was redissolved in 0.1% TFA water, acetonitrile and acetic acid until a clear solution. Depending on the solubility of the peptide, the concentration of the peptide solution was maintained at about 1 to 2 mg / ml. The peptide solution was stirred while adding iodine solution (about 1.5 equivalents) in methanol dropwise until the peptide solution obtained an orange color. After 10 to 15 minutes, oxidation was completed and excess iodine was reduced with ascorbic acid solution (1 equivalent) in water until a colorless peptide solution. Before preparative HPLC purification, the peptide solution was diluted with water.

[0825] Analytical HPLC

[0826] Final purity was determined by analytical HPLC (Agilent 1100 / 1200 series) equipped with an autosampler, degasser, 20 μl flow cell and Chromeleon software. HPLC was operated at 40°C with a flow rate of 1.2 ml / min using an analytical column (e.g. Kinetex 2.6 μm XB-C18 100A 100X8, 6 mm column). Compounds were detected and quantified at 215 nm. Buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.).

[0827] Mass spectrometry

[0828] Final MS analysis was determined on a conventional mass spectrometer (e.g., Waters Xevo G2 TOF) equipped with an electrospray detector with lock mass calibration and MassLynx software. It was operated in positive mode using direct injection and a cone voltage of 15V (1TOF), 30V (2TOF), or 45V (3TOF) as indicated in the chromatogram. The accuracy was 5ppm and the typical resolution was 15,000 to 20,000.

[0829] Synthesis of Compound No. 24 :

[0830] Ac-IC(1)IWQDWGEHRC(1)TEGE-NH2

[0831] Solid phase peptide synthesis was performed on a Symphony X synthesizer using standard Fmoc chemistry.TentaGel S RAM (2.51 g; 0.23 mmol / g) was swollen in DMF (20 ml) before use and the Fmoc-group was deprotected according to the procedure described above.

[0832] Coupling

[0833] The appropriate protected Fmoc-amino acids according to the sequence were coupled as described above using HATU as coupling reagent. All couplings were performed at RT.

[0834] Go to protection

[0835] Fmoc deprotection was performed according to the above procedure.

[0836] Cleavage of peptides from solid supports

[0837] The peptide-resin was washed with EtOH (3×10 ml) and Et2O (3×10 ml) and dried to constant weight at room temperature (roomtemperature, rt). The peptide was cleaved from the resin by treatment with TFA / DODT (95 / 5; 60 ml, 2 hours; rt). The volume of the filtrate was reduced and the crude peptide was precipitated after adding diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried to constant weight at room temperature to obtain 760 mg of crude peptide product (purity about 30%).

[0838] HPLC purification of crude linear peptides

[0839] The crude peptide was purified by preparative reverse phase HPLC using a Gilson GX-281 equipped with a 5×25 cm Gemini NX 5u C18 110A column and fraction collector with a 331 / 332 pump combination for binary gradient application and run at 35 ml / min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.) from 20% B to 45% B in 47 minutes. The fractions were analyzed by analytical HPLC and MS and the relevant fractions were combined and lyophilized to give 190 mg, 85% purity as characterized by HPLC and MS above. Calculated monoisotopic MW=2001.58, found 2001.81.

[0840] Oxidation of crude linear peptides

[0841] 190mg of the purified linear peptide was dissolved in 220ml 0.1% TFA water (65%) and acetonitrile (35%) solution until a clear solution. The peptide solution was stirred while dropwise adding an iodine solution (2.2mL, about 1.5 equivalents of iodine) in methanol until the peptide solution obtained an orange color. After the reaction, analytical HPLC was carried out, but oxidation was completed after 10 to 15 minutes. Excess iodine was reduced with an ascorbic acid solution (220 μL, about 1 equivalent) in water until a colorless peptide solution. Before purification on preparative HPLC, the peptide solution was slightly reduced by rotary evaporation.

[0842] HPLC purification of oxidized peptides

[0843] The crude peptide was purified by preparative reverse phase HPLC using a Gilson GX-281 equipped with a 5×25 cm Gemini NX 5u C18 110A column and a fraction collector with a 331 / 332 pump combination for binary gradient application and run at 35 ml / min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.) from 20% B to 45% B in 47 minutes. The fractions were analyzed by analytical HPLC and MS and the relevant fractions were combined and lyophilized to give 138 mg, 92% purity as characterized by HPLC and MS above. Calculated monoisotopic MW=1999.83, found 1999.54.

[0844] Synthesis of Compound No. 119

[0845] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu][Peg3])-NH2

[0846] Solid phase peptide synthesis was performed on a Symphony X synthesizer using standard Fmoc chemistry.TentaGel S RAM (3 x ca. 1.3 g; 0.22 mmol / g) was swollen in DMF (3 x 10 ml) before use and the Fmoc-group was deprotected according to the procedure described above.

[0847] Coupling

[0848] The appropriate protected Fmoc-amino acids according to the sequence were coupled as described above using HATU as coupling reagent. All couplings were performed at RT. The lysine used to incorporate the branching moieties was incorporated as Fmoc-Lys(Dde)-OH for orthogonal coupling.

[0849] Go to protection

[0850] Fmoc deprotection was performed according to the above procedure.

[0851] Side chain acylation

[0852] While the peptide was still attached to the resin, the orthogonal side chain protecting groups (Dde) were selectively cleaved using freshly prepared hydrazine hydrate (2% to 4%) in NMP for 2×15 min. The unprotected lysine side chain was double coupled with Fmoc-Peg3-OH, followed by single coupling with Fmoc-Glu-OtBu, Fmoc-Peg3-OH, Fmoc-Gly-OH, Fmoc-Glu-OtBu, and finally the fatty acid moiety 17-carboxy-heptadecanoic acid mono-tert-butyl ester using standard coupling conditions.

[0853] Cleavage of peptides from solid supports

[0854] The peptide-resin was washed with EtOH (3×15 ml) and Et2O (3×150 ml) and dried to constant weight at room temperature (rt). The peptide was cleaved from the resin by treatment with TFA / DODT (95 / 5; 120 ml, 2 hours; rt). The volume of the filtrate was reduced and the crude peptide was precipitated after addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried to constant weight at room temperature to give 2.36 g of crude peptide product (purity about 41% to 48%).

[0855] HPLC purification of crude linear peptides

[0856] The crude peptide was purified by preparative reverse phase HPLC using a Gilson GX-281 equipped with a 5×25 cm Gemini NX 5u C18 110A column and fraction collector with a 331 / 332 pump combination for binary gradient application and run at 35 ml / min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.) from 30% B to 60% B in 47 minutes. The fractions were analyzed by analytical HPLC and MS and the relevant fractions were combined and lyophilized to give 744 mg, 84% purity as characterized by HPLC and MS above. Calculated monoisotopic MW=3207.47, found 3207.32.

[0857] Oxidation of crude linear peptides

[0858] The linear peptide of 744mg purification is dissolved in the water of 350ml 0.1%TFA, 150ml acetonitrile and 100ml acetic acid until clear solution (cumulative volume is 600ml). Stir the peptide solution and dropwise add the iodine solution (4.7mL, about 1.5 equivalents of iodine) in methanol until the peptide solution obtains orange. After the reaction, carry out analytical HPLC, but have completed oxidation after 10 to 15 minutes. Use the ascorbic acid solution (150 μ L, about 1 equivalent) in water to reduce excessive iodine until colorless peptide solution. Slightly reduce the peptide solution by rotary evaporation before purifying on preparative HPLC.

[0859] HPLC purification of oxidized peptides

[0860] The crude peptide was purified by preparative reverse phase HPLC using a Gilson GX-281 equipped with a 5×25 cm Gemini NX 5u C18 110A column and fraction collector with a 331 / 332 pump combination for binary gradient application and run at 35 ml / min with a gradient of buffer A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.) from 30% B to 60% B in 47 minutes. The fractions were analyzed by analytical HPLC and MS and the relevant fractions were combined and lyophilized to give 510 mg, 91% purity as characterized by HPLC and MS above. Calculated monoisotopic MW=3205.47, found 3205.23.

[0861] Table 1: Synthesized compounds:

[0862]

[0863]

[0864]

[0865] Table 1 (continued):

[0866]

[0867]

[0868]

[0869] *: 4W9A—described by Mallik et al., J. Med. Chem. 2005, 48, 274-286 ("V4W / H9A").

[0870] Cp40—described by Qu et al., Immunobiology 2013, 281(4):496-505 (also referred to as “peptide 14” in this paper).

[0871] Example 2: In vitro hemolysis assay

[0872] method

[0873] The in vitro effects of the compounds of the invention were evaluated by measuring their inhibitory effects on the classical complement pathway in a hemolytic assay.

[0874] Briefly, the compounds of the invention and the reference compounds were dissolved in DMSO and diluted in Tris / casein assay buffer (10 mM Tris, 145 mM NaCl, 0.5 mM MgCl2, 0.15 mM CaCl2 and 0.1% W / V casein, adjusted to pH 7.4) as a 9-point serial dilution in a 96-well plate. Sensitized sheep red blood cells (RBCs) coated with rabbit anti-sheep red blood cell antiserum (Complement Technology, Inc., TX, USA) were washed in Tris / casein assay buffer. 50 μL of diluted compound from each well was added to a 96-well plate containing 50 μL of diluted human serum (Complement Technology, Inc., TX, USA) and incubated at room temperature for 15 minutes. The serum dilution factor was optimized for each serum batch using this protocol to obtain a maximum hemolysis of 70% to 90%. Then 50 μL of sensitized sheep red blood cells were added to all wells (10 7 ).

[0875] After incubation for 30 minutes at 37°C with gentle agitation, the reaction was terminated by adding 50 μL Tris STOP buffer (10 mM EDTA, 10 mM Tris, 145 mM NaCl, adjusted to pH 7.4) per well. RBCs were then removed by centrifugation and the resulting supernatant was measured for hemolysis by absorbance at 405 nm.

[0876] Responses were normalized to positive and negative controls (vehicle) to calculate IC50s from concentration response curves using a 4-parameter logistic (4PL) nonlinear model for curve fitting. All values ​​are based on n=>2 independent determinations.

[0877] Table 2: Exchange from valine to isoleucine. Compound 1 differs from prior art compound 4W9A only by the presence of Ile instead of Val at position 3.

[0878]

[0879] Other compounds were tested as shown below.

[0880] Table 3: In vitro analysis of hemolysis inhibition

[0881]

[0882]

[0883]

[0884] Table 3 (continued)

[0885]

[0886]

[0887] The following pairs of compounds, each differing only at position 3, show that the effects of replacing valine by isoleucine are seen in compounds with a variety of peptide backbone sequences.

[0888] Table 4: Direct comparison of Valine 3 to Isoleucine 3 when combined with modifications at positions 9, 11 and / or 13.

[0889]

[0890] It is also shown that isoleucine at position 3 is superior compared to other residues that are generally considered "conservative" substitutions for isoleucine.

[0891] Table 5: Effects of different residues at position 3 on hemolysis

[0892] Ac-IC(1) X WQDWGEHRC(1)T-NH2

[0893] Compound Position 3 (X) IC50, CP hemolysis (nM) A Valine 350 2 Isoleucine ＜100 - Leucine 500 - Norvaline ＞1000 - Norleucine 480 - Phenylalanine ＞10000 - β-Homo-Isoleucine ＞10000

[0894] Due to the high concentration of C3 present in serum, it can be difficult to distinguish between compounds with very high affinity for C3 using hemolytic assays.

[0895] In this case, a more precise degree of binding affinity to C3 can be determined by SPR measurement using immobilized C3 as described below.

[0896] Example 3: Solubility Test

[0897] Materials and Methods

[0898] The solubility of the compound is 10 mg / mL

[0899] The solubility of the compounds was assessed by measuring light scattering in the pH interval from pH 4 to pH 7.5.

[0900] Compounds were dissolved in 20 mg / mL H2O stock solutions at either pH 2.5 or pH 10. These stock solutions were diluted 1:1 with 200 mM buffer to achieve a final solution of 10 mg / mL compound in 100 mM buffer. The five conditions explored were (1) acetate pH 4.0, (2) acetate pH 5.0, (3) phosphate pH 6.0, (4) phosphate pH 7, and (5) phosphate pH 7.5.

[0901] The samples were equilibrated at ambient temperature for 15 minutes and then evaluated for solubility by visual inspection and absorbance measurement in a SpectraMax 190 microplate reader (Molecular Devices).

[0902] Visual inspection

[0903] Visual inspection involves manually checking whether the wells of the 96-well plate are clean. In addition, photos of the 96-well plate are taken.

[0904] Microplate reader and light scattering

[0905] The absorbance was measured at four wavelengths: 280 nm, 325 nm, 340 nm and 360 nm in a UV-transparent 96-well microplate in a SpectraMax 190 microplate reader (Molecular Devices). The compound does not absorb at 325 to 360 nm, and therefore the signal at these wavelengths is an expression of light scattering, which reflects the presence of visible or subvisual particles detected as increased signal.

[0906] Light scattering was normalized to the signal from pure buffer solution (100 mM) and compound solubility was assessed as good (+) or poor (-). This criterion was a combination of visual inspection and light scattering not exceeding 0.1 AU, where values ​​below 0.1 AU were good in visually clear samples.

[0907] Solubility of Compound No. 24 :

[0908] Stock solution

[0909] Compound No. 24 was carefully weighed and dissolved in pH 2.5 H2O-Cl. The stock solution was equilibrated at ambient temperature for 15 minutes, at which time no visible particles were present. A 200 mM buffer stock solution was prepared for each pH condition.

[0910] Solubility determination:

[0911] The formulations for solubility testing were prepared by mixing 50 μL of Compound No. 24 stock solution and 50 μL of buffer stock solution and gently mixing by pipetting the solution several times. The test was performed for each buffer / pH condition in a UV transparent 96-well microplate (Corning 96-well REF 3635). A reference sample without Compound No. 24 was prepared by mixing 50 μL of pH 2.5 H2O-Cl and 50 μL of buffer stock solution. The plate was covered with a lid and placed at ambient temperature for 15 minutes before evaluating solubility.

[0912] Measuring Solubility:

[0913] Solubility was assessed by visual inspection of each formulation and pictures taken in a camera box.Light scattering was measured at 280 nm, 325 nm, 340 nm and 360 nm in a SpectraMax 190 microplate reader (Molecular Devices).

[0914] Visual inspection revealed that conditions 1, 2, and 3 were turbid, and condition 2 additionally contained visible precipitate. Absorbance measurements confirmed the visual assessment that conditions 1, 2, and 3 all exceeded the 0.1 AU threshold. Therefore, conditions 4 and 5 were considered good conditions for solubility of 10 mg / mL compound No. 24.

[0915] Similarly, the solubility of other compounds was tested (Table 6).

[0916] Table 6: Table of most soluble compounds tested at 10 mg / mL. "+" indicates solubility under the given conditions, as determined by UV absorbance at 340 nm less than 0.1 AU and the sample being clear when manually inspected. "-" indicates lack of solubility under the given conditions, such as UV absorbance at 340 nm exceeding 0.1 AU and / or noticeable turbidity or containing particles.

[0917]

[0918]

[0919] Table 6 (continued)

[0920]

[0921] Example 4: Affinity measurement by surface plasmon resonance (SPR) quantity

[0922] method

[0923] Surface plasmon resonance (SPR) was used to characterize the binding affinity (Kd) of the peptides for C3. Human C3 (Complement tech cat#A113c) was immobilized on individual flow cells of a CM5 sensor chip (GE Healthcare) using standard amine coupling with a density of approximately 3000 resonance units (RU) in a buffer consisting of 10 mM phosphate pH 7.4, 150 mM NaCl, 0.05% Tween 20.

[0924] For interaction experiments, a multi-cycle experimental method was used and Biacore T200 was used. TM The device (GE Healthcare) was carried out at 25°C. The peptides were loaded in a buffer consisting of 10 mM Tris buffer (pH 7.4) with 150 mM NaCl and 0.05% Tween 20 at a flow rate of 30 μL / min in an increasing concentration series (6 to 8 different concentrations) for 60 to 120 seconds. This was followed by a dissociation period of up to 10 minutes. The C3 surface was regenerated by loading 3M MgCl2 for 45 seconds between two runs.

[0925] Sensorgrams were double referenced (reference surface, blank) to obtain association and dissociation rates for calculation of equilibrium dissociation constants, Kd, ​​before analysis of kinetic curves by global fitting of the data to a 1:1 Langmuir binding model. Each peptide was tested in at least 3 independent experiments.

[0926] Table 7: Binding affinity of compstatin analogs to C3 as determined by surface plasmon resonance assay with immobilized C3.

[0927] Compound No. Kd[nM] N 2 16 3 4 1.5 3 15 14 3 20 37 3 21 16 3 23 2.8 3 24 28 5 28 44 3 29 21 3 43 3.3 3 48 0.12 3 49 3.2 3 50 13 3 53 1.4 3 54 3.0 3 61 0.33 3 63 4.3 3 67 0.68 7 73 0.30 3 75 1.5 3 81 9.7 3 82 5.4 3 85 1.3 3 86 2.6 3

[0928] Table 7 (continued)

[0929] Compound No. Kd[nM] N 102 1.7 3 104 34 2 106 5.4 5 107 6.1 5 111 8.2 5 117 24 3 118 11 5 119 9.8 3 120 28 3 121 30 3 122 63 3 123 11 3 124 31 3 125 71 3 126 5.2 3 127 8.5 3 128 6.5 3 130 4.4 3 139 7.4 3 140 7.6 3 141 6.6 3 142 4.8 3

[0930] The following compound pairs differing only at position 3 show the effect of replacing valine by isoleucine in different peptide backbones.

[0931] Table 8: Binding affinity of compstatin analogs to immobilized C3 determined by surface plasmon resonance (SPR) assay.

[0932]

[0933] Example 5: Analysis of Test Compounds in Non-Human Primates (NHP)

[0934] Healthy male cynomolgus monkeys (Macaca fascicularis) received a single subcutaneous administration of each test substance. The compound is formulated in 20mM phosphate, adjusted to pH 7.5 with NaOH, and mannitol is used for isotonicity, and is administered with 1840nmol / kg. Blood is collected from the femoral vein of each animal at the following time: before administration, 1, 2, 4, 8, 24, 48, 72, 96 and 120 hours (10 samplings). Blood is collected in serum separation tubes and allowed to coagulate at room temperature. Test tubes are centrifuged and the resulting serum is divided equally, and quick-frozen on dry ice, and stored at nominal -80 ° C until analysis. All NHP studies are carried out according to animal welfare laws and regulations, including approval of research by local ethical review procedures.

[0935] The Complement system Alternative Pathway from Svar Life Science (formerly Eurodiagnostic AB, Sweden) was used according to the manufacturer's protocol. Kit, the serum isolated from non-human primates at a specific time point after administration is analyzed for complement activity via the alternative pathway. In short, the serum sample or control is diluted in a buffer and incubated in a microtiter strip coated with a specific activator of the alternative pathway. The wells are washed and the formed C5b-9 is detected using the included colorimetric reagent. The absorbance at 405nm is measured. The percentage activity of the alternative complement pathway is calculated for each animal and each time point relative to the activity before administration (0 hours) of the individual animal minus the negative control. This reflects the pharmacological activity of the compound.

[0936] Bypass The results of the test kit are Figure 1a to f.

[0937] exist Figure 1a Among them, the unacylated compound 61 has a relatively short duration of action despite its high affinity for C3. Figure 1b ) and compound 54 ( Figure 1e ). In contrast, when compared to the unacylated compound, although the affinity was lower, Figure 1b , 1c The acylated compounds of 1d, 1e and 1f generally have more sustained pharmacological activity in vivo. Although acylation of peptides is generally known to prolong the half-life in vivo, it was unexpectedly found that the duration of pharmacological efficacy in vivo was prolonged to this extent.

[0938] In order to estimate the pharmacokinetic half-life (t 1 / 2), serum samples isolated from non-human primates at specific time points after dosing were analyzed for total drug compounds after sample preparation by solid phase extraction (SPE) and liquid chromatography mass spectrometry (LC-MS / MS) using analog internal standards. A single measurement of serum concentration was used to calculate pharmacokinetic parameters using a non-compartmental approach in Phoenix WinNonlin 6.3. The plasma terminal elimination half-life (t 1 / 2) was determined as ln(2) / λz, where λz is the slope of the log linear regression of the log concentration versus time curve during the terminal phase.

[0939] The pharmacokinetic (PK) data are shown in Table 9.

[0940] Table 9: PK data in NHP:

[0941] Compound <![CDATA[t 1 / 2 ]]> Hour Cp40 31.8 54 9.71 61 23.3 104 96.3* 106 93.9* 107 20.1 111 157* 118 78.7* 118 155 119 139 122 127 123 105 124 112 139 82 140 100 141 145 142 143

[0942] *: Approximate determination, e.g., t determined within a period less than three times the expected half-life 1 / 2。

Claims

1. A compstatin analog which is: Ac-IC(1)IWQDWGEHRC(1)T-NH2(Compound 2) Ac-ESSAIC(1)IWQDWGEHRC(1)T-NH2(Compound 3) Ac-IC(1)l[1-Me-Trp]QDWGEHRC(1)T-NH2(Compound 4) Ac-IC(1)IWQKWGEHRC(1)T-NH2(Compound 7) Ac-YC(1)IWQDWGEHRC(1)T-NH2(Compound 9) Ac-ESSAYC(1)IWQDWGEHRC(1)T-NH2(Compound 10) Ac-[Sar]C(1)IWQDWGEHRC(1)T-NH2(Compound 11) Ac-IC(1)IWQDWGEHRC(1)[Sar]-NH2(Compound 13) Ac-ESSAIC(1)IWQDWGEHRC(1)TGAES-NH2(Compound 14) Ac-IC(1)IWQDWGEHRC(1)TGAES-NH2(Compound 15) Ac-IC(1)IWQEWGEHRC(1)T-NH2(Compound 16) Ac-IC(1)IWQDWGEHSC(1)T-NH2(Compound 20) Ac-IC(1)IWQDWGEHRC(1)S-NH2(Compound 21) Ac-IC(1)IWQDWGEHRC(1)E-NH2(Compound 22) Ac-FC(1)IWQDWGEHRC(1)T-NH2(Compound 23) Ac-IC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 24) Ac-IC(1)IWQDWGEHRC(1)TEA-NH2(Compound 25) Ac-IC(1)IWQDWGEHRC(1)TE-NH2(Compound 26) Ac-IC(1)IWQDWGEHRC(1)EGE-NH2(Compound 27) Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 28) Ac-EGSAIC(1)IWQDWGEHRC(1)T-NH2(Compound 29) Ac-EGEIC(1)IWQDWGEHRC(1)T-NH2(Compound 30) Ac-ESEIC(1)IWQDWGEHRC(1)T-NH2(Compound 31) Ac-SEIC(1)IWQDWGEHRC(1)TEA-NH2(Compound 32) Ac-EIC(1)IWQDWGEHRC(1)TE-NH2(Compound 33) Ac-EIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 34) Ac-EGEIC(1)IWQDWGEHRC(1)EGE-NH2(Compound 35) Ac-ESEIC(1)IWQDWGEHRC(1)EGE-NH2(Compound 36) Ac-KEKIC(1)IWQDWGEHRC(1)TEKE-NH2(Compound 37) Ac-EKGIC(1)iWQDWGEHRC(1)TEKP-NH2(Compound 38) Ac-IC(1)IWQDWGEHRC(1)TEGK-NH2(Compound 39) Ac-GSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 40) Ac-SAIC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 41) Ac-SAIC(1)IWQDWGEHRC(1)TEG-NH2(Compound 42) Ac-FC(1)IWQDWGEHRC(1)TGAE-NH2(Compound 43) Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]EGE-NH2(Compound 44) Ac-EGSAFC(1)IWQDWGEHRC(1)[Sar]E-NH2(Compound 45) Ac-EGSAIC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2(Compound 49) Ac-EGSAIC(1)I[2-Nal]QDWGEHRC(1)[Sar]E-NH2(Compound 50) Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2(Compound 51) Ac-IC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2(Compound 52) Ac-EGSAFC(1)|[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2(Compound 53) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 54) Ac-EGSAIC(1)IWQDWGEHRC(1)TE-NH2(Compound 55) Ac-EGSAFC(1)I[1-Nal]QDWGEHRC(1)TE-NH2(Compound 56) Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 57) Ac-EGSAFC(1)|[1-Me-Trp]QDWGEHRC(1)EGE-NH2(Compound 58) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 59) Ac-EGSAFC(1)I[2-Nal]QDWGEHRC(1)TE-NH2(Compound 60) Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2(Compound 61) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 62) Ac-FC(1)I[1-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 63) Ac-FC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 64) Ac-YC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 65) Ac-YC(1)IWQDWGEHRC(1)TGAES-NH2 (Compound 66) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 67) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS-NH2 (Compound 68) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA-NH2 (Compound 69) Ac-EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E-NH2 (Compound 70) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 71) Ac-FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 72) H-{d}YFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 73) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES-NH2 (Compound 74) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 75) Ac-SEFC(1)i[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]EA-NH2 (Compound 76) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TEA-NH2 (Compound 77) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 78) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E-NH2 (Compound 79) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 80) Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 81) Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 82) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 83) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)SEA-NH2 (Compound 84) Ac-EFC(1)i[1-Me-Trp]QDWGEHRC(1)ES-NH2 (Compound 85) Ac-SEFC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]EA-NH2 (Compound 86) Ac-GEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 87) Ac-GE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 88) Ac-SE[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)TEA-NH2(Compound 89) Ac-SE[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 90) or H-{d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 91) or a pharmaceutically acceptable salt thereof; Wherein {d}Y represents D-tyrosine; And the side chain of the residue indicated as "C(1)" participates in a disulfide bond.

2. A compstatin analog which is: Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH2(Compound 92) Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 93) Ac-IC(1)IWQDWGEHRC(1)TEGE-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 94) Ac-IC(1)IWQDWGEHRC(1)TEG-K((15-carboxy-pentadecanoyl)-[(piperazin-1-yl)-acetyl][Peg3][Peg3])-NH2(Compound 95) Ac-IC(1)IWQDWGEHRC(1)TEG-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH2(Compound 96) Ac-IC(1)IWQDWGEHRC(1)TEGE-K([17-carboxy-heptadecanoyl][γGIu][Peg3][Peg3])-NH2(Compound 97) Ac-IC(1)IWQDWGEHRC(1)TEG-K([19-carboxy-nonadecanoyl][γGIu][Peg3][Peg3])-NH2(Compound 98) [15-Carboxy-pentadecanoyl]-ESSAIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 99)Ac-[K([15-Carboxy-pentadecanoyl]- [γGlu][Peg3][Peg3])]GSAIC(1)IWQDWGEHRC(1)TEGE-NH2(Compound 100)Ac-EGSAIC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH2(Compound 101) Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2 (Compound 102) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEH-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-C(1)[Sar]E-NH2 (Compound 103) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH2 (Compound 104) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([17-carboxy-heptadecanoyl][γGlu]KG[γGlu])-NH2 (Compound 105) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 106) [15-Carboxy-pentadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 107) [17-Carboxy-heptadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 108) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 109) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 110) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])]-NH2(Compound 111) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])]-NH2 (Compound 112) Ac-ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu)-G[γGlu])-NH2 (Compound 113) Ac-SEYC(1)|[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2(Compound 114) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 115) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-K[γGlu])-NH2 (Compound 116) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 117) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[Peg3][γGlu][Peg3])-NH2 (Compound 118) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[Peg3][γGlu][Peg3])-NH2(Compound 119) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[Peg3][γGlu][Peg3])-NH2(Compound 120) Ac-SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]AK([17-carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu]-[Peg3])-NH2 (Compound 121) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G-[Peg3][γGlu][Peg3])-NH2 (Compound 122) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 123) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 124) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 125) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 126) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K[(15-carboxy-pentadecanoyl)[γGlu]G[γGlu]])-NH2 (Compound 127) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K[(19-carboxy-nonadecanoyl)[γGlu]G[γGlu])-NH2 (Compound 128) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-K([17-carboxy-heptadecanoyl 1-[γGlu]G[γGlu])-NH2(Compound 129) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 130) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-K([15-carboxy-pentadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 131) Ac-SEFC(1)i[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 132) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 133) Ac-EFC(1)l[1-Me-Trp]QDWGEHRC(1)EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 134) Ac-SEFC(1)I[1-Me-Trp]QDWWGEHRC(1)TGAES-K([15-carboxy-hexadecanoyl][γGlu]G[γGlu])-NH2(Compound 135) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEG E[8-aminooctanoyl]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 136) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]EK([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2(Compound 137) Ac-SEFC(1)I[1-Me-Trp]QDVVGEHRC(1)[Sar]EGE[Peg3]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH2 (Compound 138) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH2(Compound 139) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 140) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl][γGlu])-NH2(Compound 141) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu])-NH2(Compound 142) Ac-SEFC(1)I[1-Me-Trp]QDWGEHR[C(1)[Sar]EGE[Peg3][Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 143) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 144) or Ac-EF[C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH2 (Compound 145) or a pharmaceutically acceptable salt thereof; The side chain of the residue indicated as "C(1)" participates in a sulfide bond.

3. A composition comprising a compstatin analog or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2 in admixture with a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compstatin analog or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2 in admixture with a pharmaceutically acceptable carrier.

5. A compstatin analog or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2 for use in therapy.

6. An ex vivo method of inhibiting complement activation during in vitro diversion of a physiological fluid, the method comprising contacting the physiological fluid with a compstatin analog according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, thereby inhibiting complement activation.

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