title: Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.
abstract: The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
authors.affiliation: RI CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Barker
authors.forename: Margaret
authors.initials: M
authors.lastname: Clackers
authors.forename: Royston
authors.initials: R
authors.lastname: Copley
authors.forename: Derek A
authors.initials: DA
authors.lastname: Demaine
authors.forename: Davina
authors.initials: D
authors.lastname: Humphreys
authors.forename: Graham G A
authors.initials: GG
authors.lastname: Inglis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johnston
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Jones
authors.forename: Michael V
authors.initials: MV
authors.lastname: Haase
authors.forename: David
authors.initials: D
authors.lastname: House
authors.forename: Richard
authors.initials: R
authors.lastname: Loiseau
authors.forename: Lesley
authors.initials: L
authors.lastname: Nisbet
authors.forename: Francois
authors.initials: F
authors.lastname: Pacquet
authors.forename: Philip A
authors.initials: PA
authors.lastname: Skone
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Shanahan
authors.forename: Dan
authors.initials: D
authors.lastname: Tape
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Vinader
authors.forename: Melanie
authors.initials: M
authors.lastname: Washington
authors.forename: Iain
authors.initials: I
authors.lastname: Uings
authors.forename: Richard
authors.initials: R
authors.lastname: Upton
authors.forename: Iain M
authors.initials: IM
authors.lastname: McLay
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D011965:Receptors, Glucocorticoid; D013764:Tetrahydronaphthalenes; D003907:Dexamethasone