R Sarabu, J P Cooper, C M Cook, P Gillespie, A V Perrotta, G L Olson
{"title":"Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template.","authors":"R Sarabu, J P Cooper, C M Cook, P Gillespie, A V Perrotta, G L Olson","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 3","pages":"191-8"},"PeriodicalIF":0.0000,"publicationDate":"1998-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug design and discovery","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
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.