Abstract
Imidazole and oxazole derivatives 1 to 4 were designed and prepared as dipeptide mimetics to replace the Ser-Leu dipeptide sequence of Ro-25-9980 (Ac-(Cha)-RAMA- S - L -NH 2 ), a peptidic inhibitor of antigen binding to major histocompatibility complex (MHC) class II DR molecules linked to rheumatoid arthritis (RA). The most potent analog in binding assays (IC 50 = 30 nM in DRB1*0401 binding; 1.6 times as potent as Ro 25-9980) was 16 , Ac-(Cha)RAMA-( S ) S - Ψ (oxazole)- L -NH 2 . The SAR of peptide hybrids 10 to 24 , prepared by incorporating the dipeptide mimetics 1 to 4 is discussed. Of these hybrids, 23 and 24 , analogs that incorporated the imidazole and oxazole mimetics as well as optimized variants at positions 3 to 5, were found to have 70 to 80 nM binding affinity comparable to the parent peptide in DRB1*0401 binding and were also active in DRB1*0101 binding, while being resistant to proteolysis by cathepsin B. Both of these compounds showed inhibitory activity in an antigen-stimulated T-cell proliferation assay, indicating their potential to suppress autoimmune responses and as leads for therapeutic agents to treat RA.