P-selectin targeting ligand and compositions thereof

摘要

A P-selectin targeting ligand molecule (I) comprising target-recognizing group formed from a peptide, peptoid or its derivative, a spacer formed from water-soluble oligomer or polymer, and an anchoring moiety formed from an amphiphilic lipid consisting of one or more hydrophobic apolar moiety and a hydrophilic polar head group, is new. A P-selectin targeting ligand molecule (I) comprises a target-recognizing moiety, which is formed from a peptide, peptoid or its derivative, a spacer formed from a water-soluble oligomer or polymer, and an anchoring moiety, which is formed from an amphiphilic lipid consisting of one or more hydrophobic apolar moiety and a hydrophilic polar head group, where the target-recognizing moiety has an amino acid sequence X(A x) mA 3A 1A 2A 1Y, or its function equivalent, A 1D- or L-cysteine, D- or L-methionine, D- or L-valine, or its analog; A 2D- or L-aspartic acid or its analog; A 3D- or L-phenylalanine, D- or L-tyrosine, D- or L-tryptophan, or its analog; A xD- or L-amino acid; X : N-terminal side of the sequence (optionally substituted by R 1>-(Z) n-); Y : C-terminal side of the sequence (optionally substituted by R 1>-(Z) n-); X+Y : cyclic system (optionally substituted by R 1>-(Z) n-); Z : CO, O, NR 2>or CO-NR 2>; R 1>and R 2>H, 1-8C alkyl group, 2-8C alkyl group (in which one or more C-atom is replaced with N, O or S), 6-14C aryl group (optionally substituted with halogen), 1-6C alkyl, -CF 3, -OH, -O-1-6C alkyl, -COOH, -COO-1-6C alkyl, -NO 2, -NH 2, -NH-1-6C alkyl, -N(1-6C alkyl) 2or -SO 3H, heteroaryl (optionally substituted with one or more of halogen, 1-6C alkyl, -CF 3, -OH, -O-1-6C alkyl, -COOH, -COO-1-6C alkyl, -NO 2, -NH 2, -NH-1-6C alkyl, -N(1-6C alkyl) 2or -SO 3H), or an aralkyl group comprising an alkyl, aryl or heteroaryl group; and m and n : 0 or 1. Provided that n is not 0 when R 1>is H. Independent claims are also included for: (1) a pharmaceutical composition (II) comprising a carrier, and one or more (I) associated with the surface of the carrier; and (2) a kit for preparing (II), comprising a liquid and a solid component, where the liquid component is an aqueous composition, and the solid component comprises a colloidal carrier and one or more (I), being prepared by conventional methods and subsequent removal of water. ACTIVITY : Cardiant; Vasotropic; Anticoagulant; Thrombolytic; Cytostatic; Antiinflammatory; Antirheumatic; Antiarthritic; Gastrointestinal-Gen.; Neuroprotective; Antiarteriosclerotic; Nephrotropic; Vulnerary; Antibacterial; Immunosuppressive; Respiratory-Gen.; Cerebroprotective; Antiangiogenic. No biological data given. MECHANISM OF ACTION : Inactivates P-selectin; Counteracts inflammatory process within P-selectin activated cells.