Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy.
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.
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
Nicole
N
Lounsbury
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
George
G
Mateo
Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA.
Brielle
B
Jones
Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA.
Srinivas
S
Papaiahgari
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Rajash K
RK
Thimmulappa
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.
Christiana
C
Teijaro
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
John
J
Gordon
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
Kenneth
K
Korzekwa
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
Min
M
Ye
Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA.
Graham
G
Allaway
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
Magid
M
Abou-Gharbia
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.
Shyam
S
Biswal
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA. Electronic address: wayne.childers@temple.edu.
Wayne
W
Childers
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D002599:Chalcone / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012995:Solubility
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D002599:Chalcone; D051547:Heme Oxygenase-1
Bioavailability; Chalcone; Keap1; Nrf2; Solubility