Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template

The interleukin-1 proteins (IL-1α and IL-1β) are key mediators of inflammatory and immunological responses and several in vitro and in vivo studies with protein-based antagonists have demonstrated the potential usefulness of IL-I receptor antagonists to treat various inflammation related diseases. Based on the X-ray crystal structures of IL-1 ligands and site-directed mutagenesis data, a noncontiguous binding epitope encompassing Arg 4 , Phe 46 , Ile 56 , Lys 93 , Lys 103 , and Glu 105 for IL-1β was proposed. In this paper we describe the synthesis and binding assay results of small molecule IL-I receptor antagonists designed on the basis of the three-dimensional structure of the binding epitope. Among these. the compound 45 was found to inhibit IL-α binding to the Type I receptor with an IC 50 value of 3 μM. A hypothesis generated using BioCad CATALYST program is also presented to rationalize these observations.