title: Discovery of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogs as new RORC modulators.
abstract: Structure-based and pharmacophore-based virtual screening in combination with combinatorial chemistry and X-ray crystallography led to the discovery of a new class of benzothiadiazole dioxide analogs with functional activity as RORC inverse agonists. The early RORC SAR compound 14 exhibited RORC inhibition in a cell based reporter gene assay of 5.7 μM and bound to RORC with an affinity of 1.6 μM in a fluorescence polarization assay displacing a ligand binding site probe. Crystallography confirmed the binding mode of the compound in the ligand binding domain displaying the engagement of a novel sub pocket close to Ser404. Subsequent optimization yielded compounds with enhanced RORC inverse agonist activity. The most active compound 19 showed an IC50 of 440 nM in a human PBMC assay.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: ingo.mugge@boehringer-ingelheim.com.
authors.forename: Ingo
authors.initials: I
authors.lastname: Muegge
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Collin
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cook
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Horan
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Kugler
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Labadia
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Lana
authors.initials: L
authors.lastname: Smith
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000604977:1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; D052160:Benzothiazoles; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: Combinatorial chemistry; Crystal structure; Retinoid orphan receptor; Virtual screening