PharmPK Discussion - Michael's addition reaction in biological environment-

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On 4 Sep 2000 at 15:05:30, "NVSRAO MAMIDI" (mamidi_nvsrao.aaa.hotmail.com) sent the message


Hi all :

I would like to know the cases where compound is undergoing Michael's
addition reaction in biological enviornment (in-vivo or in-vitro
plasma)and its further discovery and development was dropped because
of these reasons/stability issues.
Any information/literature on this subject is highly appreciated.
Thanking you in anticipation.
Mamidi S Rao

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On 5 Sep 2000 at 15:55:45, Alexander.Treiber.aaa.Actelion.Com sent the message


Dear Mamidi,

one example is tienilic acid, a diuretic drug that was withdrawn from
the market due to idiosyncratic liver toxicity. The drug contains a
thiophene moiety that is described in the literature to be activated
by CYP 2C9 to a putative thiophene sulfoxides. The resulting Michael
acceptor system is thought to covalently bind to CYP 2C9 subsequently
triggering the events leading to the rare observed cases of fulminant
hepatotoxicity. For more details refer to Mansuy et al (most papers
from the mid 90s). More examples are found in the class of
bioactivated furan derivatives, e.g. menthofuran.

Best regards
Alex

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