Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators
Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators
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DOI：
10.1016/j.bmcl.2019.126852
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发表时间：
2020-02-15
影响因子：
2.7
通讯作者：
Richter, Karl
中科院分区：
文献类型：
--
作者：
Ma, Bin;Lucas, Brian;Richter, Karl
Nrf 2是调节II相抗氧化反应表达的转录因子，在神经保护和解毒中起重要作用。Nrf 2的激活通过与Keap 1的相互作用而被抑制。共价Keap 1抑制剂如富马酸二甲酯（DMF）和RTA-408已上市或处于后期临床试验中，这意味着Nrf 2激活的潜在益处。通过非共价小分子破坏Nrf 2-Keap 1相互作用来激活Nrf 2是一种有吸引力的方法，具有更大的选择性。然而，没有已知的具有可接受的药代动力学性质的非共价Nrf 2激活剂来在体内测试该假设。基于我们早期报道的工作，使用基于结构的设计，然后进行广泛的SAR探索，我们已经确定了一系列新的非共价Nrf 2激活剂，在星形胶质细胞测定中对Keap 1具有亚纳摩尔结合亲和力和个位数纳摩尔活性。代表性类似物在肾脏中显示出优异的口服PK和良好的Nrf 2依赖性基因诱导。这些结果提供了外周体内工具化合物来验证Nrf 2的非共价活化的生物学。
Nrf2 is a transcription factor regulating expression of the Phase II Antioxidant Response and plays an important role in neuroprotection and detoxification. Nrf2 activation is inhibited by interaction with Keap1. Covalent Keap1 inhibitors such as dimethyl fumarate (DMF) and RTA-408 are either on the market or in late stage clinical trials which implies potential benefit of Nrf2 activation. Activation of Nrf2 by disrupting Nrf2-Keap1 interaction through a non-covalent small molecule is an attractive approach with the promise of greater selectivity. However, there are no known non-covalent Nrf2 activators with acceptable pharmacokinetic properties to test the hypothesis in vivo. Based on our early reported work, using structural-based design, followed by extensive SAR exploration, we have identified a novel series of non-covalent Nrf2 activators, with sub-nanomolar binding affinity on Keap1 and single digit nanomolar activity in an astrocyte assay. A representative analog shows excellent oral PK and good Nrf2-dependent gene inductions in kidney. These results provide a peripheral in vivo tool compound to validate the biology of non-covalent activation of Nrf2.