US2022162261A1PendingUtilityA1
NOVEL a4B7 PEPTIDE MONOMER AND DIMER ANTAGONISTS
Assignee: PROTAGONIST THERAPEUTICS INCPriority: Oct 1, 2014Filed: Jul 16, 2021Published: May 26, 2022
Est. expiryOct 1, 2034(~8.2 yrs left)· nominal 20-yr term from priority
A61P 37/02C07K 7/08A61K 38/00A61P 19/02A61P 29/02A61P 25/04A61P 1/00A61P 15/00C07K 7/06A61P 31/18A61P 1/04A61P 1/16A61P 7/00A61P 1/18A61P 25/00A61P 37/06A61P 11/02A61P 19/10A61P 35/00C07K 14/7051A61P 11/00A61P 25/24A61P 11/06A61P 3/10A61P 29/00A61P 43/00A61P 3/04
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Claims
Abstract
The invention relates to peptide dimer compounds and peptide monomer compounds that potently inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, possess high selectivity against α4β1 binding, and have high stability under gastrointestinal conditions.
Claims
exact text as granted — not AI-modified1 . A peptide dimer compound comprising two linked monomer subunits of Formula (I):
(Formula (I))
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -
Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14
or a pharmaceutically acceptable salt thereof,
wherein:
Xaa 1 is absent, Ac, or any amino acid;
Xaa 2 is absent, Ac, or any amino acid;
Xaa 3 is absent, Ac, or any amino acid;
Xaa 4 is Pen or Cys;
Xaa 5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidinoguanidino), Phe(4-carbomyl), Cit, Phe(4-NH 2 ), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;
Xaa 6 is Ser, Ile, Gly, Thr or Ile;
Xaa 7 is Asp, Asp(OMe) or N-Me-Asp;
Xaa 8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;
Xaa 9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, cyclopentylAla, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;
Xaa 10 is Pen;
Xaa 11 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, and Tic;
Xaa 12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, Homo-Phe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;
Xaa 13 is absent or Pro or any amino acid; and
Xaa 14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, HomoGlu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp;
wherein:
Xaa 5 is selected from the group consisting of Cit, Phe(4-carbomylamino), and N-Me-homoArg;
Xaa 8 is selected from the group consisting of Leu, homoLeu, Nle and Val;
Xaa 9 is selected from the group consisting of Cba, homoLeu, and Cpa;
Xaa 11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu);
Xaa 12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; or
Xaa 13 is Pro; and
wherein one or both monomer subunits of the peptide dimer compound comprises a disulfide bond between Xaa 4 and Xaa 10 .
2 . The peptide dimer compound of claim 1 , further comprising a linker moiety linking the two monomer subunits, wherein the linker moiety is optionally selected from the group consisting of DIG, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, cyclopropylacetic acid, 4-fluoorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, biotin, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, aliphatic amino acids, aromatic amino acids, heteroaromatics, polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da, bifunctional linkers, N-Hydroxy succinamine (NHS)-activated diesters, and bis-maleimides.
3 . The peptide dimer compound of claim 2 , wherein the N-terminus of each monomer subunit is linked by the linker moiety to provide an N-terminus dimer compound.
4 . The peptide dimer compound of claim 2 , wherein the C-terminus of each monomer subunit is joined by the linker moiety to provide a C-terminus dimer compound.
5 . The peptide dimer compound of claim 1 , wherein Xaa 5 is N-Me-Arg.
6 . The peptide dimer compound of claim 1 , wherein Xaa 6 is Ser, Xaa 7 is Asp, Xaa 8 is Thr, and/or Xaa 9 is Leu.
7 . The peptide dimer compound of claim 1 , wherein Xaa 11 is Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), or Phe(4-tBu).
8 . The peptide dimer compound of claim 1 , wherein:
Xaa 5 is N-Methyl-Arg; Xaa 6 is Ser; Xaa 7 is Asp; Xaa 8 is Thr or Val; Xaa 9 is Leu; Xaa 11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF 3 ), Phe(4-CH 3 ). Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, β-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), and HomoPhe; Xaa 12 is selected from the group consisting of: any aromatic amino acid, Glu, D-Glu, and beta-homoGlu; Xaa 13 is absent; and Xaa 14 is selected from the group consisting of: D-Lys, N-Me-Lys, and D-N-Me-Lys.
9 . The peptide dimer compound of claim 8 , wherein both subunits comprise one of the following sequences:
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys);
or
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys),
wherein the subunits are linked via their C-termini, optionally wherein the subunits are linked via a DIG linker.
10 .- 11 . (canceled)
12 . The peptide dimer compound of claim 9 , wherein the peptide dimer compound has one of the following structures:
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys)-
NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys)-
NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys)-NH 2 ] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-l-Nal-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-l-Nal-(β-homoGlu)-(N-Me-Lys)-NH 2 ] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys)-
OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys)-OH] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys)-
OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys)-OH] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(N-Me-Lys)-OH] 2 -
DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-NH 2 ] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-l-Nal-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-l-Nal-(β-homoGlu)-OH] 2 -DIG;
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH] 2 -DIG;
or
[Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-OH] 2 -DIG.
13 . The peptide dimer compound of claim 12 , wherein the peptide dimer compound is an acetate salt.
14 . The peptide dimer compound of claim 1 , wherein the peptide dimer compound a C-terminal OH.
15 . The peptide dimer compound of claim 1 , further comprising N(alpha)methylation at one or more positions selected from the group consisting of Xaa 3 , Xaa 5 , Xaa 7 -Xaa 9 , and Xaa 11 -Xaa 13 .
16 . The peptide dimer compound of claim 1 , further comprising acylation at one or more position selected from the group consisting of Xaa 1 -Xaa 3 and Xaa 11 -Xaa 14 .
17 .- 18 . (canceled)
19 . A peptide monomer compound of Formula (IV):
(Formula (IV))
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -
Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14
or a pharmaceutically acceptable salt thereof,
wherein:
Xaa 1 is absent, Ac, or any amino acid;
Xaa 2 is absent, Ac, or any amino acid;
Xaa 3 is absent, Ac, or any amino acid;
Xaa 4 is Pen and Cys;
Xaa 5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidino), Phe(4-carbomylamino), Cit, Phe(4-NH 2 ), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;
Xaa 6 is Ser Gly, Thr, or Ile;
Xaa 7 is Asp, Asp(OMe), or N-Me-Asp;
Xaa 8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;
Xaa 9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, cyclopentylAla, Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;
Xaa 10 is Pen;
Xaa 11 is absent or selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF 3 ), Phe(4-CH 3 ), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, aromatic amino acids, substituted aromatic amino acids, and Tic;
Xaa 12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, Homo-Phe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;
Xaa 13 is absent or Pro or any amino acid; and
Xaa 14 is any amino acid,
wherein
Xaa 5 is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-HomoArg;
Xaa 8 is selected from the group consisting of Leu, homoLeu, Nle and Val;
Xaa 9 is selected from the group consisting of: Cba, homoLeu, and Cpa;
Xaa 11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu);
Xaa 12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; or
Xaa 13 is Pro; and
wherein the peptide monomer compound comprises a disulfide bond between Xaa 4 and Xaa 10 or
a peptide monomer compound of Formula (V):
(Formula (V))
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10
or a pharmaceutically acceptable salt thereof,
wherein the peptide compound comprises a disulfide bond Xaa 1 and Xaa 7 ;
wherein Xaa 1 -Xaa 10 of Formula (V) corresponds to Xaa 4 -Xaa 13 of Formula (IV), and wherein
Xaa 1 is Pen;
Xaa 2 is selected from the group consisting of Cit, Phe(4-carbonyl), and N-Me-HomoArg;
Xaa 3 is Ser Gly, Thr, or Ile;
Xaa 4 is Asp, D-Asp, Asp(OMe), or N-Me-Asp;
Xaa 5 is selected from the group consisting of Leu, HomoLeu, Nle and Val;
Xaa 6 is selected from the group consisting of, Cba, HomoLeu, and Cpa;
Xaa 7 is Pen;
Xaa 8 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu),
Xaa 9 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; and
Xaa 10 is Pro.
20 .- 22 . (canceled)
23 . The peptide monomer compound of claim 19 , wherein the peptide monomer compound comprises one of the following sequences or structures:
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(13-homo-Glu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-(P-homo-Glu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(13-homo-Glu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(N-Me-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys);
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(N-Me-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-(N-Me-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-(D-Lys)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys)-NH 2 ;
or
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(β-homo-Glu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu;
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-(β-homo-Glu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu;
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu;
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(β-homo-Glu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu;
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu);
Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-OH;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β-homoGlu)-NH 2 ;
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β-homoGlu)-NH 2 ;
or
Ac-Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-NH 2 .
24 .- 26 . (canceled)
27 . A method for treating a subject afflicted with a condition that is associated with a biological function of an α4β7 integrin, the method comprising administering to the human an effective amount of a compound of claim 1 .
28 .- 41 . (canceled)Join the waitlist — get patent alerts
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