TEMPLATE-FIXED PEPTIDOMIMETICS AS INHIBITORS OF FPR1

摘要

Novel template-fixed β-hairpin peptidomimetics of the general formula (I): cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-T1-T2] wherein the single elements T or P are α-amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property of antagonizing the biological effect of the receptor FPR1. They can be used as medicaments to treat or prevent diseases or conditions in the areas of inflammatory diseases, allergic conditions, immunological disorders, neuroinflammation, neurological disorders, obstructive airway diseases, infectious diseases, ischemic reperfusion injuries and proliferative disorders such as e.g. cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

主权项

1. A compound of the general formula (I),
cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-T1-T2]  (I) wherein the single elements T or P are connected in either direction from the carbonyl (C═O) point of attachment to the nitrogen (N) of the next element and wherein T1 is a naturally or non-naturally occurring D α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; T2 is a naturally or non-naturally occurring L α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P1, P3, P12, P13 and P14 are independently Gly or a naturally or non-naturally occurring L α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P2, P5 and P8 are independently a naturally or non-naturally occurring aromatic L α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P4 and PH are naturally or non-naturally occurring cross-linking L α-amino acids containing each in total 1 to 12 carbon- and/or heteroatoms in a single side-chain which together are connecting P4 and P11 by covalent or electrostatic interaction; P6 is Gly; P7 is a naturally or non-naturally occurring D α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P9 is a naturally or non-naturally occurring alcoholic L α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; and P10 is a naturally or non-naturally occurring aliphatic L α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; or a tautomer or rotamer thereof, or a salt, or a hydrate or solvate thereof.