1254035-86-3Relevant academic research and scientific papers
Hip to Be Square: Oxetanes as Design Elements to Alter Metabolic Pathways
Toselli, Francesca,Fredenwall, Marlene,Svensson, Peder,Li, Xue-Qing,Johansson, Anders,Weidolf, Lars,Hayes, Martin A.
, p. 7383 - 7399 (2019/08/20)
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.
THERAPEUTIC AGENTS 713
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Page/Page column 46, (2010/11/17)
Disclosed herein are compounds of Formula (I) in which R1, R2, R3, R4, R5, A, X, Y are as described in the specification, their use in pharmaceutical compositions and in methods of treatment or prophylaxis of a melanin-concentrating hormone related disease or condition.
