Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators.

Autor: Ma B; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: bin.ma@biogen.com., Lucas B; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Capacci A; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Lin EY; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Jones JH; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Dechantsreiter M; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Enyedy I; Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Marcotte D; Biophysics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Xiao G; Drug Metabolism & Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Li B; Research & Early Development, Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Richter K; Research & Early Development, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Feb 15; Vol. 30 (4), pp. 126852. Date of Electronic Publication: 2019 Dec 02.
DOI: 10.1016/j.bmcl.2019.126852
Abstrakt: 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.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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