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

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 sui...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (16), p.3891-3897
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.06.048