title: Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists.
abstract: A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure-activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
authors: Benjamin P
authors: BP
authors: Fauber
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Alberto
authors: A
authors: Gobbi
authors: Argenta, Discovery Services, Charles River, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors: Pascal
authors: P
authors: Savy
authors: Argenta, Discovery Services, Charles River, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors: Brenda
authors: B
authors: Burton
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Yuzhong
authors: Y
authors: Deng
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Christine
authors: C
authors: Everett
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Hank
authors: H
authors: La
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Adam R
authors: AR
authors: Johnson
authors: Argenta, Discovery Services, Charles River, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors: Peter
authors: P
authors: Lockey
authors: Argenta, Discovery Services, Charles River, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors: Maxine
authors: M
authors: Norman
authors: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Harvey
authors: H
authors: Wong
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000607754:N-sulfonyl-tetrahydroquinoline; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011804:Quinolines; C539900:RORC protein, human
keywords: Autoimmune; IL-17; Inflammation; RORc; RORγ