Non-steroidal glucocorticoid agonists - The discovery of aryl pyrazoles as A-ring mimetics

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 NF kappa B agonism pIC(50) 8-8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NF kappa B 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. (c) 2007 Elsevier Ltd. All rights reserved.