title: Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist.
abstract: Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.forename: Olivier
authors.initials: O
authors.lastname: René
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: ⊥Discovery Biology, Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Arunima
authors.initials: A
authors.lastname: Ganguli
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.affiliation: ⊥Discovery Biology, Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: ⊥Discovery Biology, Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: Lockey
authors.affiliation: ⊥Discovery Biology, Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Maxine
authors.initials: M
authors.lastname: Norman
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: ⊥Discovery Biology, Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Susan
authors.initials: S
authors.lastname: Summerhill
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003499:Cyclic S-Oxides / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013843:Thiazines / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: C000601735:1-(4-(3-fluoro-4-(3-methyl-1,1-dioxo-6-phenyl(1,2)thiazinan-2-ylmethyl)phenyl)piperazin-1-yl)ethanone; D003499:Cyclic S-Oxides; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D013449:Sulfonamides; D013843:Thiazines; C480101:beta-sultam