title: Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists.
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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: René
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: de Leon Boenig
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Brenda
authors.initials: B
authors.lastname: Burton
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Lockey
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Maxine
authors.initials: M
authors.lastname: Norman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001798:Blood Proteins / Q000737:chemistry* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001798:Blood Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D013449:Sulfonamides
keywords: IL-17; Permeability; RORc; RORγ; Solubility; X-ray structure