Patent WO-2021009204-A1 (WO)
Inventor: HEINIS CHRISTIAN
IPC: C07K14/81
Filed: 2020-07-15
Abstract: The present invention relates to a cyclic inhibitor of a kallikrein protease comprising or consisting of (I) the peptide (X 1  (X 2 )(X 3 )R(X 4 )(X 5 )(X 6 )(X 7 )(X 8 )(X 9 )(X 10 )(X 11 ) (Formula (X)), wherein (X 1 ) is present or absent and, is preferably present, and if present, is an amino acid, and is most preferably D-alanine or G; (X 2 ) is an amino acid with a side chain; (X 3 ) is an amino acid with a polar uncharged side chain, is preferably with a polar uncharged side chain comprising a hydroxyl group, is more preferably T or S and is most preferably T; (X 4 ) is an amino acid, preferably citrulline, Q or E; (X 5 ) is an amino acid, preferably an amino acid with a hydrophobic side chain; (X 6 ) is present or absent, is preferably absent, and, if present, is an amino acid with a negatively charged side chain, preferably D; (X 7 ) is present or absent, is preferably present, and, if present, is an amino acid, more preferably an amino acid with a side chain comprising a pyrrole of indole, even more preferably P, hydroxyl-proline, (R)-3- piperidine carboxylic acid or W, and most preferably P; (X 8 ) is present or absent and, if present, is an amino acid, and is preferably absent; (X 9 ) is present or absent and, if present, is an amino acid, and is preferably absent; (X 10 ) is an amino acid with a side chain; and (X 11 ) is present or absent and, if present, is an amino acid, and is preferably absent; wherein the side chains of (X 2 ) and (X 10 ) are connected via a connecting molecule, said connecting molecule having at least two functional groups, each functional group forming a covalent bond with one of the side chains of (X 2 ) and (X 10 ); and wherein the kallikrein protease is Kallikrein-related peptidase (KLK5); or (II) the peptide (Y 1 )(Y 2 )(Y 3 )(Y 4 )(Y 5 )(Y 6 )(Y 7 )(Y 8 )(Y 9 ) (Formula (Y)), wherein (Y 1 ) is present or absent, is preferably present, and, if present, is an amino acid, preferably P, L-beta-hydroxyl-proline, D-proline, (R)-3-piperidine carboxylic acid, Q or R, and is most preferably P; (Y 2 ) is an amino acid with a side chain; (Y 3 ) is I, L or L- Neopentylglycine, and is preferably L; (Y 4 ) is Y or F, and is preferably Y; (Y 5 ) is an amino acid, preferably an amino acid with a hydrophobic side chain, or Q or R, is more preferably L, norleucine, Q, I, R or M, and is most preferably norleucine or L; (Y 6 ) is an amino acid, preferably an amino acid with a hydrophobic side chain and is most preferably A; (Y 7 ) is absent or present, preferably present and, if present, is an amino acid preferably Q, homoarginine, 4-guanidino-phenlalanine or R; (Y 8 ) is an amino acid with a side chain; and (Y 9 ) is present or absent and, if present, is an amino acid, preferably S, and is most preferably absent; wherein the side chains of (Y 2 ) and (Y 8 ) are connected via a connecting molecule, said connecting molecule having at least two functional groups, each functional group forming a covalent bond with one of the side chains of (Y 2 ) and (Y 8 ); and wherein the kallikrein protease is Kallikrein-related peptidase 7 (KLK7).