Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template.
The interleukin-1 proteins (IL-1 alpha and IL-1 beta) 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-1 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 Arg4, Phe46, Ile56, Lys93, Lys103, and Glu105 for IL-1 beta was proposed. In this paper we describe the synthesis and binding assay results of small molecule IL-1 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-alpha binding to the Type I receptor with an IC50 value of 3 microM. A hypothesis generated using BioCad CATALYST program is also presented to rationalize these observations.
Department of Inflammation and Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
R
R
Sarabu
J P
JP
Cooper
C M
CM
Cook
P
P
Gillespie
A V
AV
Perrotta
G L
GL
Olson
D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002384:Catalysis; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D008958:Models, Molecular; D008968:Molecular Conformation; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D017472:Receptors, Interleukin-1