Download MendeleyReduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists.
Fauber, B.P., Rene, O., de Leon Boenig, G., Burton, B., Deng, Y., Eidenschenk, C., Everett, C., Gobbi, A., Hymowitz, S.G., Johnson, A.R., La, H., Liimatta, M., Lockey, P., Norman, M., Ouyang, W., Wang, W., Wong, H.(2014) Bioorg Med Chem Lett 24: 3891-3897
- PubMed: 25017032
- DOI: https://doi.org/10.1016/j.bmcl.2014.06.048
- Primary Citation of Related Structures:
4QM0 - PubMed 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.
Organizational Affiliation:
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
