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

Bin Ma; Brian Lucas; Andrew Capacci; Edward Yin-Shiang Lin; John Howard Jones; Michael Dechantsreiter; Istvan Enyedy; Douglas Marcotte; Guangqing Xiao; Bing Li; Karl Richter

doi:10.1016/j.bmcl.2019.126852

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

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126852. doi: 10.1016/j.bmcl.2019.126852. Epub 2019 Dec 2.

Authors

Affiliations

¹ Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: bin.ma@biogen.com.
² Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
³ Biophysics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁴ Drug Metabolism & Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁵ Research & Early Development, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.

PMID: 31898999
DOI: 10.1016/j.bmcl.2019.126852

Abstract

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.

Keywords: Astrocyte; Gene induction; Keap1; Non-covalent activator; Nrf2; PPI; X-ray.

MeSH terms

Administration, Oral
Animals
Astrocytes / cytology
Astrocytes / drug effects
Astrocytes / metabolism
Brain / metabolism
Drug Design*
Half-Life
Humans
Kelch-Like ECH-Associated Protein 1 / chemistry
Kelch-Like ECH-Associated Protein 1 / metabolism
Kidney / metabolism
Mice
NF-E2-Related Factor 2 / agonists*
NF-E2-Related Factor 2 / metabolism
Protein Interaction Domains and Motifs
Rats
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacokinetics
Small Molecule Libraries / pharmacology
Structure-Activity Relationship

Substances

KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Small Molecule Libraries