| 摘要 |
The VLA-4 (Very Late Antigen of activation-4, also known as alpha-4-beta-1 integrin) inhibitor has the basic formula A-B, wherein A comprises a VLA-4 specificity determinant, and B comprises an integrin scaffold derived from a compound having IIb/IIIa activity. Examples of groups from which A is selected include; alkyl, aliphatic acyl optionally substituted with N-alkyl or N-arylamido, aroyl, heterocycloyl, alkylaminocarbonyl, alkyl- and arylsulfonyl, aralkylcarbonyl optionally substituted with aryl, heterocycloalkylcarbonyl or other group. Formulae IIa, IIb and IIc represent examples of compounds from which B is selected. A1 is NR1, O, S, (CR1R2)r or N[(CR1R2)m(C=Y)A2R1]; A3 is O, NR2, S or (CR1R2)r; X is H2, O or S; m is 1-4; n is 0-5; W is CO2H, SO3H, PO4H2, tetrazole or H; U is COR12, (CR1R2)n R12 or SO2R11; R1 and R2 are independently H, optionally substituted alkyl, alkenyl, cycloalkenyl, heterocycle or other group; R3 is R1 or amino acid side chain; R5 and R6 are independently H, OR1, halogen, alkyl, SR1, NZR12 or NR1R2; r is 0 or 1; A2 is O, NR2, S or (CR1R2)r; Y is H2 or O; Z is CO or CR1R2)n; R11 is optionally substituted alkyl, cycloalkyl, alkenyl, aryl, heterocycle or other group; R12 is H, optionally substituted alkyl, cycloalkyl, aryl, heterocycle or other group. The inhibitor has an IC50 of 1pM to 10uM as measured by a VLA-4 direct binding assay. A medicament comprising the compounds of formulae A-B can be used as therapeutic or prophylactic agents for the treatment of inflammatory and autoimmune diseases, asthma, adult respiratory distress syndrome, multiple sclerosis and diabetes. The IIb/IIIa inhibitor has the basic formula X-Y, wherein X comprises a IIb/IIIa specificity determinant and Y comprises an integrin scaffold derived from a VLA-4 inhibitor.
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