Tricyclic Compounds Containing Non-enolizable Cyano Enones. A Novel Class of Highly Potent Anti-inflammatory and Cytoprotective Agents

Forty-four novel tricycles containing non-enolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in Phase II clinical trials for the treatment of severe chronic kidney disease in di...

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Veröffentlicht in:Journal of medicinal chemistry 2011-03, Vol.54 (6), p.1762-1778
Hauptverfasser: Honda, Tadashi, Yoshizawa, Hidenori, Sundararajan, Chitra, David, Emilie, Lajoie, Marc J., Favaloro, Frank G., Janosik, Tomasz, Su, Xiaobo, Honda, Yukiko, Roebuck, Bill D., Gribble, Gordon W.
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Sprache:eng
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Zusammenfassung:Forty-four novel tricycles containing non-enolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in Phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of non-enolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ, and highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4b S ,8a R ,10a S )-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)- 31 ) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton, but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm101445p