Literature DB >> 25815138

Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

Olivier René1, Benjamin P Fauber1, Gladys de Leon Boenig1, Brenda Burton2, Céline Eidenschenk1, Christine Everett1, Alberto Gobbi1, Sarah G Hymowitz1, Adam R Johnson1, James R Kiefer1, Marya Liimatta1, Peter Lockey2, Maxine Norman2, Wenjun Ouyang1, Heidi A Wallweber1, Harvey Wong1.   

Abstract

A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

Entities:  

Keywords:  IL-17; PBMC; RORc; RORγ; TH17; agonist; inverse agonist

Year:  2014        PMID： 25815138      PMCID： PMC4360161          DOI： 10.1021/ml500420y

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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