2023
DOI: 10.1021/acsmedchemlett.3c00067
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Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1–Nrf2 PPI Inhibitor

Abstract: Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1–Nrf2 protein–protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor 7 with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully p… Show more

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Cited by 8 publications
(11 citation statements)
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“…The syntheses of compounds 9 – 14 were performed following the procedure described in Scheme . Corresponding aryl acetic acids 35a – f were coupled with chiral β-amino-ester 36 which was prepared according to our previously reported procedure . The resulting tert -butyl esters 37a – f were treated with HCl to provide 9 – 14 .…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…The syntheses of compounds 9 – 14 were performed following the procedure described in Scheme . Corresponding aryl acetic acids 35a – f were coupled with chiral β-amino-ester 36 which was prepared according to our previously reported procedure . The resulting tert -butyl esters 37a – f were treated with HCl to provide 9 – 14 .…”
Section: Resultsmentioning
confidence: 99%
“…We have recently identified a novel noncovalent Keap1-Nrf2 inhibitor 8 that showed an increase in oxidative stress suppressing proteins in kidneys (Figure ). In the previous structure–activity relationship (SAR) campaign, starting from the β-amino acid compound 7 with comparable high metabolic stability, solubility, and permeability, we found a unique α-fluoroamide moiety to interact with a polar residue without loss of membrane permeability, unlike other polar functional groups. Thus, the lead compound 8 , which contained the 3-α-fluoroamido-3-phenylpropanoic acid moiety, exhibited excellent physicochemical properties and therefore demonstrated the highest oral bioavailability among the reported noncovalent Keap1-Nrf2 inhibitors observed so far.…”
Section: Introductionmentioning
confidence: 96%
“…Most importantly, compound 39 displayed robust PK profiles and had the best oral bioavailability among the previously reported Keap1–Nrf2 inhibitors (F = 136%). In both human renal mesangial cells and rat kidneys, compound 39 could provoke a significant increase in the protein level of Nrf2-regulated HO-1 …”
Section: Recent Progress Of Small-molecule Keap1–nrf2 Ppi Inhibitorsmentioning
confidence: 99%
“…119 Not long ago, another set of phenylpropanoic acid-based analogs was disclosed as Keap1−Nrf2 inhibitors that maintained great drug-like properties. 120 At the beginning of this research, a Biacore-based HTS of the in-house chemical library was conducted, resulting in the identification of a hit compound 36 (Figure 7A) with weak Keap1−Nrf2 inhibitory activity (Biacore: IC 50 = 40 μM) and favorable drug properties. Subsequently, the researchers compared both enantiomers of 36 for inhibitory activity, confirming that the (S)-enantiomer 37 (Figure 7A) was active (Biacore: IC 50 = 39 μM).…”
Section: Recent Progress Of Small-molecule Keap1−nrf2 Ppi Inhibitorsmentioning
confidence: 99%
“…24 However, due to the plasticity of the Keap1 binding site, they can target different conformations of the Keap1 protein, and represent a complementary approach to Keap1/Nrf2 inhibition. 25–30 Consequently, the development of a cell permeable Nrf2-like peptide that retains activity in the cellular environment would be a significant breakthrough. Herein, we describe a variety of Cys dependant stapling approaches of an Nrf2 peptide, of which the divinylpyrimidine (DVP) 31 two-component peptide stapling (2C-PS) approach proved particularly useful to easily access a variety of peptides of different sizes carrying different functionalities.…”
Section: Introductionmentioning
confidence: 99%