C5a Receptor Antagonists

摘要

Cyclic or acyclic peptide or peptidomimetic compounds (I), (II) or (III), typically hexapeptides and generally having a C-terminal aminoacid (or derivative or analog) residue, are new. Peptide or peptidomimetic compounds of formulae (I), (II) and (III). X1-X2-X3-X4-X5-X6-X7-X8 (I) [Image] [Image] X1 : group of molecular weight 1-300, preferably selected from R5, R5CO, R5N(R6)CO, R5OCO, R5SO 2, R5N(R6)SO 2, R5N(R6), R5N(R6)CS, R5N(R6)C(=NH), R5CS, R5P(O)(OH), R5B(OH) or R5CH=NOCH 2CO; R5, R6 : H, F, OH or (all optionally substituted) alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl, heteroaryl, acyl, alkoxy, alkoxyalkyl or aryloxyalkyl; X2 : group mimicking the biological binding properties of a phenylalanine unit; X3, X4 : spacer, preferably an aminoacid (or derivative or analog) residue; X5 : group mimicking the biological binding properties of a cyclohexylalanine unit; X6 : group mimicking the biological binding properties of a tryptophan unit; X7 : group mimicking the biological binding properties of a norleucine or phenylalanine unit; X8 : H, NH 2, OH, NHOH, heteroaryl, aminoacid (or derivative or analog) residue, absent or amino, alkoxy, hydrazino, aminooxy, alkyl, cycloalkyl, heterocyclyl, heteroaryl, aralkyl, aryl (all optionally substituted); d1 - d4 : spacings of A, B, C and D in at least one energetically accessible conformer of (II), such that (i) d1 = 5.1 1.0 Å, d2 = 11.5 1.0 Å, d3 = 10.0 1.5 Å and d4 = 6.9 1.5 Å or (ii) d1, d2 = 3.9 0.5 Å and d3, d4 = 9.0 1.5 Å; A, B, C, D : C-alpha -atoms in aminoacid (or derivative or analog) residues; A, C : hydrophobic aminoacid side-chains selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; B, D : aromatic or heteroaromatic side-chains selected from aryl and heteroaryl; A chemical bond is optionally present between X3 and X7; the bonds in (I) are chemical bonds, preferably selected from covalent, ionic and coordinative bond, especially bonds forming amide, disulfide, ether, thioether, oxime or aminotriazine linkages. ACTIVITY : Antirheumatic; antiarthritic; dermatological; immunosuppressive; neuroprotective; antipsoriatic; antibacterial; antiasthmatic; vasotropic; antiinflammatory; cerebroprotective; cardiant; vulnerary; thrombolytic; nephrotrophic. MECHANISM OF ACTION : C5a receptor antagonist; complement inhibitor. Ac-Phe-(Orn-Pro-cha-Trp-Eaf) (Ia) had IC 5 0 5-10 nM in a C5a receptor antagonist assay.