Svensson P

References (2)

Title : Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways - Toselli_2019_J.Med.Chem_62_7383
Author(s) : Toselli F , Fredenwall M , Svensson P , Li XQ , Johansson A , Weidolf L , Hayes MA
Ref : Journal of Medicinal Chemistry , 62 :7383 , 2019
Abstract : Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that contribute to drug metabolism is important since an exaggerated dependence on one specific isoenzyme increases the risk of drug-drug interactions with co-administered drugs. Herein, we illustrate that mEH-catalyzed hydrolysis is an important metabolic pathway for a set of more structurally diverse oxetanes and the degree of hydrolysis is modulated by minor structural modifications. A homology model based on the Bombyx mori EH crystal structure was used to rationalize substrate binding. This study shows that oxetanes can be used as drug design elements for directing metabolic clearance via mEH, thus potentially decreasing the dependence on cytochromes P450. Metabolism by mEH should be assessed early in the design process to understand the complete metabolic fate of oxetane-containing compounds, and further study is required to allow accurate pharmacokinetic predictions of its substrates.
ESTHER : Toselli_2019_J.Med.Chem_62_7383
PubMedSearch : Toselli_2019_J.Med.Chem_62_7383
PubMedID: 31310524

Title : Oxetane Substrates of Human Microsomal Epoxide Hydrolase - Toselli_2017_Drug.Metab.Dispos_45_966
Author(s) : Toselli F , Fredenwall M , Svensson P , Li XQ , Johansson A , Weidolf L , Hayes MA
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 45 :966 , 2017
Abstract : 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 pKa in the vicinity of the oxetane and an increased distance between the oxetane ring and the benzylic nitrogen improve reaction rate, which is further enhanced by the presence of methyl groups near or on the oxetane. This work defines oxetanes as the first nonepoxide class of substrates for human mEH, which was previously known to catalyze the hydrolytic ring opening of electrophilic and potentially toxic epoxide-containing drugs, drug metabolites, and exogenous organochemicals. These findings will be of value for the development of biologically active oxetanes and may be exploited for the biocatalytic generation of enantiomerically pure oxetanes and diols.
ESTHER : Toselli_2017_Drug.Metab.Dispos_45_966
PubMedSearch : Toselli_2017_Drug.Metab.Dispos_45_966
PubMedID: 28600384