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. 2014 Dec 4;6(3):276-81.
doi: 10.1021/ml500420y. eCollection 2015 Mar 12.

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

Olivier René  1 , Benjamin P Fauber  1 , Gladys de Leon Boenig  1 , Brenda Burton  2 , Céline Eidenschenk  1 , Christine Everett  1 , Alberto Gobbi  1 , Sarah G Hymowitz  1 , Adam R Johnson  1 , James R Kiefer  1 , Marya Liimatta  1 , Peter Lockey  2 , Maxine Norman  2 , Wenjun Ouyang  1 , Heidi A Wallweber  1 , Harvey Wong  1
Affiliations

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

Olivier René et al. ACS Med Chem Lett. .

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.

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

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Evolution of Genentech’s tertiary sulfonamide RORc modulators.
Figure 2
Figure 2
Binding modes of agonist ligand 3 and inverse agonist ligand 2 within the ligand binding pocket of RORc. The crystal structure of the agonist ligand 3 (purple ribbon) stabilized helix 12 and revealed a coactivator peptide (green) bound to the receptor. The crystal structure of the inverse agonist ligand 2 (yellow ribbon) did not have resolved density for helices 11–12. Concerted motions of Trp317, Phe486 and His479 are depicted with arrows.
Scheme 1
Scheme 1. Synthesis of Sulfonamides 3, 4, and 9–33
Reagents and conditions: (a) Pd(OAc)2, RuPhos, NaOt-Bu, 1,4-dioxane, 100 °C; (b) HCl, H2O, THF, 23 °C, 60% (2 steps); (c) cyclobutylamine, NaBH(OAc)3, AcOH, 1,2-DCE, 23 °C, quant.; (d) R-SO2Cl, DIPEA, CH2Cl2, 23 °C, 29–57%.
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