Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6604-9. doi: 10.1016/j.bmcl.2013.10.054.

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

Affiliations

Affiliation

1 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.

PMID: 24239186 DOI: 10.1016/j.bmcl.2013.10.054

Abstract

The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against Other nuclear receptors.

Keywords

Autoimmune; IL-17; Inflammation; RORc; RORγ; T0901317; X-ray structure.

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