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Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics |
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| Authors: | Clackers Margaret Coe Diane M Demaine Derek A Hardy George W Humphreys Davina Inglis Graham G A Johnston Michael J Jones Haydn T House David Loiseau Richard Minick Doug J Skone Philip A Uings Iain McLay Iain M Macdonald Simon J F |
| Affiliation: | Medicines Research Centre, riCEDD, GlaxoSmithKline, Stevenage, UK. |
| 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. |
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