Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action
ACS Medicinal Chemistry Letters2014Vol. 6(3), pp. 276–281
Citations Over TimeTop 10% of 2014 papers
Olivier René, Benjamin P. Fauber, Gladys de Leon Boenig, Brenda Burton, Céline Eidenschenk, Christine Everett, Alberto Gobbi, S.G. Hymowitz, Adam R. Johnson, James R. Kiefer, Marya Liimatta, Peter Lockey, Maxine Norman, Wenjun Ouyang, Heidi Ackerly Wallweber, Harvey Wong
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.
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