Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators was written by Ma, Bin;Lucas, Brian;Capacci, Andrew;Lin, Edward Yin-Shiang;Jones, John Howard;Dechantsreiter, Michael;Enyedy, Istvan;Marcotte, Douglas;Xiao, Guangqing;Li, Bing;Richter, Karl. And the article was included in Bioorganic & Medicinal Chemistry Letters in 2020.Formula: C20H30BNO4 This article mentions the following:
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 di-Me fumarate (DMF) and RTA-408 are either on the market or in late stage clin. trials which implies potential benefit of Nrf2 activation. Activation of Nrf2 by disrupting Nrf2-Keap1 interaction through a non-covalent small mol. 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 biol. of non-covalent activation of Nrf2. In the experiment, the researchers used many compounds, for example, tert-Butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (cas: 937048-76-5Formula: C20H30BNO4).
tert-Butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (cas: 937048-76-5) belongs to isoquinoline derivatives. Quinoline and its derivatives are widely used as fungicides, biological agents, antibiotics, alkaloids, dyes, rubber chemicals and flavoring agents. Lewis acid activation and nucleophilic attack can produce multiple regioisomers in quinolines and pyridines; isoquinolines generally only undergo attack at the 1-position.Formula: C20H30BNO4
Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem