title: Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties.
abstract: Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: rene.olivier@gene.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: René
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Barnard
authors.affiliation: Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: Chapman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Maxine
authors.initials: M
authors.lastname: Norman
authors.affiliation: Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Salmon
authors.affiliation: Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Summerhill
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D055808:Drug Discovery; D054314:Drug Inverse Agonism; D008055:Lipids / Q000737:chemistry*; D009282:Naphthalenesulfonates / Q000737:chemistry; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000819:agonists*
chemical_list: D008055:Lipids; D009282:Naphthalenesulfonates; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C016768:naphthosultone
keywords: IL-17; Inverse agonist; Oxa-sultam; PBMCs; RORc; RORγ