Novel inhibitors of kallikrein proteases and uses thereof
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 5 (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).
67437750
Alternative title(s) : (de) Neuartige inhibitoren von kallikreinproteasen und verwendungen davon (fr) Nouveaux inhibiteurs de protéases de kallicréine et leurs utilisations
TTO:6.1944
TTO:6.1944.1
Patent number | Country code | Kind code | Date issued |
EP3766894 | EP | A1 | 2021-01-20 |