title: Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.
abstract: Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
authors.affiliation: Medicines Research Centre, riCEDD, GlaxoSmithKline, Stevenage, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Clackers
authors.forename: Diane M
authors.initials: DM
authors.lastname: Coe
authors.forename: Derek A
authors.initials: DA
authors.lastname: Demaine
authors.forename: George W
authors.initials: GW
authors.lastname: Hardy
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: David
authors.initials: D
authors.lastname: House
authors.forename: Richard
authors.initials: R
authors.lastname: Loiseau
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Minick
authors.forename: Philip A
authors.initials: PA
authors.lastname: Skone
authors.forename: Iain
authors.initials: I
authors.lastname: Uings
authors.forename: Iain M
authors.initials: IM
authors.lastname: McLay
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
mesh_terms: D000577:Amides / Q000737:chemistry; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000819:agonists*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D011720:Pyrazoles / Q000737:chemistry*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry
chemical_list: D000577:Amides; D005938:Glucocorticoids; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; D013256:Steroids