非甾体糖皮质激素激动剂：作为A环模拟物的芳基吡唑的发现。
Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.
作者信息
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
机构信息
Medicines Research Centre, riCEDD, GlaxoSmithKline, Stevenage, UK.
出版信息
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4737-45. doi: 10.1016/j.bmcl.2007.06.066. Epub 2007 Jun 26.
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.
从一系列已确立的非甾体糖皮质激素受体（GR）激动剂出发，设计了一个大型化合物库，其中代谢不稳定的苯并恶嗪酮部分被取代。最初筛选得到的化合物与GR结合，但缺乏激动剂活性。经过另外两轮迭代，发现了强效GR激动剂，其中20D1E1具有NFκB激动作用，pIC(50)为8.8（103%）。其他类似物如23D1E1表现出解离的特征（NFκB pIC(50)为8.1（103%），MMTV pEC(50)为7.02（36%））。四氢萘部分也可以被取代芳基如24E1和25E1所取代。
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