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

• Published in: Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (16), p.3891-3897
• Main Authors: Fauber, Benjamin P., René, Olivier, de Leon Boenig, Gladys, Burton, Brenda, Deng, Yuzhong, Eidenschenk, Céline, Everett, Christine, Gobbi, Alberto, Hymowitz, Sarah G., Johnson, Adam R., La, Hank, Liimatta, Marya, Lockey, Peter, Norman, Maxine, Ouyang, Wenjun, Wang, Weiru, Wong, Harvey
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; BASIC BIOLOGICAL SCIENCES; Binding Sites - drug effects; Blood Proteins - chemistry; Blood Proteins - metabolism; Cell Membrane Permeability - drug effects; Crystallography, X-Ray; Dogs; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; IL-17; Madin Darby Canine Kidney Cells; Models, Molecular; Molecular Structure; Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Permeability; Rats; RORc; RORγ; Solubility; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; X-ray structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.06.048

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.