Bioanalysis of syn dimeric HIV-1 protease inhibitor N-benzyl 4-aryl-1,4-dihydropyridine H19: metabolic and cytotoxic properties in Hep G2 cells.
Syn dimeric N-benzyl 4-aryl-1,4-dihydropyridine H19 is a nonpeptidic HIV-1 protease inhibitor of the dihydroxyethylene type representing novel C2-symmetric inhibitors. Great interest was focussed on the extent of metabolism of these novel inhibitory structures as their functional groups are similar to certain peptidic and non-peptidic HIV-1 protease inhibitors with poor bioavailability due to extensive metabolism. Thus, early characterization of metabolic and toxic properties decisively determines the future prospects of those novel HIV-1 protease inhibitors. Both metabolism and toxicity were evaluated in Hep G2 monolayers. While no phase-I metabolites were found the extent of conjugation in phase-II of biotransformation was poor. Moreover, cytotoxic evaluation of protein and DNA decrease and, furthermore, of membrane toxicity characterized the novel inhibitors as non-toxic. Consequently, the favourable poor metabolism and non-toxic properties encourage further development of these novel HIV-1 protease inhibitors.
Hilgeroth
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Institut für Pharmazeutische Chemie der Martin-Luther-Universität Halle-Wittenberg, Germany.
Langner
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D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D007770:L-Lactate Dehydrogenase; D016333:HIV Protease