Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3891-7. doi: 10.1016/j.bmcl.2014.06.048.

Benjamin P Fauber ¹, Olivier René ², Gladys de Leon Boenig ², Brenda Burton ³, Yuzhong Deng ², Céline Eidenschenk ², Christine Everett ², Alberto Gobbi ², Sarah G Hymowitz ², Adam R Johnson ², Hank La ², Marya Liimatta ², Peter Lockey ³, Maxine Norman ³, Wenjun Ouyang ², Weiru Wang ², Harvey Wong ²

Affiliations

1 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
2 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3 Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.

PMID: 25017032 DOI: 10.1016/j.bmcl.2014.06.048

Abstract

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over Other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility.

Keywords

IL-17; Permeability; RORc; RORγ; Solubility; X-ray structure.

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