Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy

Nicole Lounsbury; George Mateo; Brielle Jones; Srinivas Papaiahgari; Rajash K Thimmulappa; Christiana Teijaro; John Gordon; Kenneth Korzekwa; Min Ye; Graham Allaway; Magid Abou-Gharbia; Shyam Biswal; Wayne Childers Jr

doi:10.1016/j.bmc.2015.07.056

Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy

Bioorg Med Chem. 2015 Sep 1;23(17):5352-9. doi: 10.1016/j.bmc.2015.07.056. Epub 2015 Jul 29.

Affiliations

¹ Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
² Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA.
³ Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
⁴ Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.
⁵ Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA. Electronic address: sbilwal@jhsph.edu.
⁶ Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA. Electronic address: wayne.childers@temple.edu.

PMID: 26278028
DOI: 10.1016/j.bmc.2015.07.056

Abstract

Nrf2 activators represent a good drug target for designing agents to treat diseases associated with oxidative stress. Building upon previous work, we designed and prepared a series of heterocyclic chalcone-based Nrf2 activators with reduced lipophilicity and, in some cases, greater in vitro potency compared to the respective carbocyclic scaffold. These changes resulted in enhanced oral bioavailability and a superior pharmacodynamic effect in vivo.

Keywords: Bioavailability; Chalcone; Keap1; Nrf2; Solubility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antioxidants / administration & dosage
Antioxidants / chemistry*
Antioxidants / pharmacokinetics
Antioxidants / pharmacology*
Caco-2 Cells
Cell Line
Chalcone / administration & dosage
Chalcone / chemistry*
Chalcone / pharmacokinetics
Chalcone / pharmacology*
Female
Gene Expression Regulation / drug effects
Heme Oxygenase-1 / analysis
Heme Oxygenase-1 / genetics
Humans
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2 / agonists*
NF-E2-Related Factor 2 / metabolism
Oxidative Stress / drug effects
Solubility

Substances

Antioxidants
NF-E2-Related Factor 2
NFE2L2 protein, human
Nfe2l2 protein, mouse
Chalcone
Heme Oxygenase-1