Optimization of 3-Aminotetrahydrothiophene 1,1-Dioxides with Improved Potency and Efficacy as Non-Electrophilic Antioxidant Response Element (ARE) Activators

6 Pages Posted: 8 Mar 2023

See all articles by Jeyun Jo

Jeyun Jo

Pusan National University

Jisu Kim

Pusan National University

Lara Ibrahim

The Scripps Research Institute

Manoj Kumar

California Institute for Biomedical Research

Jonathan Iaconelli

The Scripps Research Institute

Cong So Tran

Pusan National University

Hyung Ryoung Moon

Pusan National University

Yunjin Jung

Pusan National University

R. Luke Wiseman

The Scripps Research Institute - Department of Molecular Medicine

Luke L. Lairson

The Scripps Research Institute

Arnab Chatterjee

The Scripps Research Institute

Michael J. Bollong

The Scripps Research Institute

Hwayoung Yun

Pusan National University

Abstract

Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.

Keywords: ARE activator, NRF2, Non-electrophilic, PGK1 inhibitor, Drug-likeness

Suggested Citation

Jo, Jeyun and Kim, Jisu and Ibrahim, Lara and Kumar, Manoj and Iaconelli, Jonathan and Tran, Cong So and Moon, Hyung Ryoung and Jung, Yunjin and Wiseman, R. Luke and Lairson, Luke L. and Chatterjee, Arnab and Bollong, Michael J. and Yun, Hwayoung, Optimization of 3-Aminotetrahydrothiophene 1,1-Dioxides with Improved Potency and Efficacy as Non-Electrophilic Antioxidant Response Element (ARE) Activators. Available at SSRN: https://ssrn.com/abstract=4370327 or http://dx.doi.org/10.2139/ssrn.4370327

Jeyun Jo

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

Jisu Kim

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

Lara Ibrahim

The Scripps Research Institute ( email )

United States

Manoj Kumar

California Institute for Biomedical Research ( email )

Jonathan Iaconelli

The Scripps Research Institute ( email )

United States

Cong So Tran

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

Hyung Ryoung Moon

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

Yunjin Jung

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

R. Luke Wiseman

The Scripps Research Institute - Department of Molecular Medicine ( email )

United States

Luke L. Lairson

The Scripps Research Institute ( email )

United States

Arnab Chatterjee

The Scripps Research Institute

Michael J. Bollong

The Scripps Research Institute ( email )

United States

Hwayoung Yun (Contact Author)

Pusan National University ( email )

mulgeumup beomyeli
Pusan 609-735, 50612
Korea, Republic of (South Korea)

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