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Merck

Oxetane Substrates of Human Microsomal Epoxide Hydrolase.

Drug metabolism and disposition: the biological fate of chemicals (2017-06-11)
Francesca Toselli, Marlene Fredenwall, Peder Svensson, Xue-Qing Li, Anders Johansson, Lars Weidolf, Martin A Hayes
RÉSUMÉ

Oxetanyl building blocks are increasingly used in drug discovery because of the improved drug-like properties they confer on drug candidates, yet little is currently known about their biotransformation. A series of oxetane-containing analogs was studied and we provide the first direct evidence of oxetane hydrolysis by human recombinant microsomal epoxide hydrolase (mEH). Incubations with human liver fractions and hepatocytes were performed with and without inhibitors of cytochrome P450 (P450), mEH and soluble epoxide hydrolase (sEH). Reaction dependence on NADPH was investigated in subcellular fractions. A full kinetic characterization of oxetane hydrolysis is presented, in both human liver microsomes and human recombinant mEH. In human liver fractions and hepatocytes, hydrolysis by mEH was the only oxetane ring-opening metabolic route, with no contribution from sEH or from cytochrome P450-catalyzed oxidation. Minimally altering the structural elements in the immediate vicinity of the oxetane can greatly modulate the efficiency of hydrolytic ring cleavage. In particular, higher p

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Description du produit

Sigma-Aldrich
Hydrobenzoin
Sigma-Aldrich
cis-Stilbene oxide, 97%
Sigma-Aldrich
Valpromide, ≥97% (NMR)