| 摘要 |
New sialic acid-binding Ig-like lectin (Siglec) inhibitors comprise of neuraminic acid derivatives (including aza, carba or thia analogs) (I) containing an optionally substituted amino group at the terminal of the side-chain (i.e. the C-9 position). New sialic acid-binding Ig-like lectin (Siglec) inhibitors comprise of neuraminic acid derivatives or analogs of formula (I); X = negatively charged group, such as carboxy, phosphate, sulfate or their derivatives; Y = H, alkyl, aryl, OH, glycan, polymeric carrier or a derivative; Z' = O, N, C or S; R1 = H, OH or a derivative; R2 = OH, NH2 or a derivative; R3 = OH or a derivative; R4 (hydrogen acceptor) = OH or a derivative; R5 (hydrogen donor) = amino, optionally substituted by optionally substituted formyl, alkanoyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkyl, aryl, cycloalkyl or heteroaryl (or analogs containing one or more unsaturated bonds); R6, R'6 = H, alkyl, a charged group or a derivative, provided that at least one of R6 and R'6 is a hydrophobic group (preferably H or Me); R7 = H or a substituent (specifically a group improving the pharmacological properties of the Siglec inhibitor). Independent claims are also included for: (1) a method for increasing the binding specificity of Siglec inhibitors, comprising introducing a group R5 as defined above in the position corresponding to R5 in neuraminic acid or its derivative; and (2) a method for preparing Siglec inhibitors with increased affinity for a Siglec molecule, comprising: (a) introducing a group R5 as defined above in the position corresponding to R5 in neuraminic acid or its derivative; (b) determining the affinity for a Siglec molecule; (c) selecting the products with increased activity; and optionally (d) varying the substituents in other positions (especially R2).
|
