Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.
Kazuki OtakeMinoru UbukataNoboru NagahashiNaoki OgawaYoshiji HantaniRie HantaniTsuyoshi AdachiAkihiro NomuraKeishi YamaguchiMariko MaekawaHideaki MamadaTakahisa MotomuraMotohide SatoKazuhito HaradaPublished in: ACS medicinal chemistry letters (2023)
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 provided the lead compound 25 , which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting 25 , which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys.
Keyphrases
- protein protein
- oxidative stress
- chronic kidney disease
- small molecule
- end stage renal disease
- diabetic rats
- ischemia reperfusion injury
- dna damage
- induced apoptosis
- positron emission tomography
- mental health
- computed tomography
- cell proliferation
- combination therapy
- transcription factor
- risk assessment
- heat shock
- smoking cessation