Ezetimibe metabolism

Metaboiism/Excretion- Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. 

C4 promoted the preinstallation of these metabolically productive functionalities. Coupling the above observations, it became clear to us to simultaneously optimize all regions of the structure and target what is now known as ezetimibe (1) (Rosenblum et al., 1998). As the S AR was developed with an in vivo assay, improvement in activity reflected a complex balance between intrinsic receptor affinity and ADME considerations. We now appreciate that the site of action is the enterocyte on the intestinal villi, and thus systemic absorption is not required for activity. The above outlined combination of synthetic organic... 

Myotoxicity linked to ezetimibe has been described in a 45-year-old overweight man with McArdle disease, which is the most common disorder of muscle carbohydrate metabolism, caused by mutations in the gene that encodes myophosphorylase (5). 

As far as research collaboration is concerned, the Schering-Plough manufacturing process for its cholesterol absorption inhibitor, Ezetimibe (Zetia), exemplifies the collaboration case. The close interaction between Research and Development, aided by the delay caused by the realization that the first API structure (XVI) had to be modified to overcome metabolism issues, provided the intellectual resource and the time for a fuller understanding of the chemistry needed to create the chiral (3-lactam ring. 

Muraoka T, Aoki K, Iwasaki T, Shinoda K, Nakamura A, Aburatani H, Mori S, Tokuyama K, Kubota N, Kadowaki T, Terauchi Y (2011) Ezetimibe decreases SREBP-lc expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet. Metabolism 60 617-628... 

Scheme 4.12 Examples of fluorine

Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe a review of its metabolism, pharmacokinetics, and drug interactions. Clin Pharmacokinet 2005 44 467-494. 

For example, van Heek and coworkers observed a lead candidate that underwent extensive first-pass metabolism and yet elicited a significant level of pharmacological activity (van Heek et al., 1997). To evaluate the biological activity of the in vivo biotransformation products, they collected samples of bile from rats dosed with a lead compound and directly administered the samples to a bile duct cannulated rats via an intraduodenal cannula. As a control study, the parent compound prepared in a blank bile was dosed in a similar fashion to the recipient rats. The results indicated that the in vivo activity elicited by the bile samples was higher than the parent control sample, clearly indicating the presence of an active metabolite(s) that was more potent than the parent compound. To identify the active component, the bile sample was then fractionated and each fraction tested for biological activity. The structure of the metabolite was then established following the detection of the active fraction. As mentioned before, further modification of the active metabolite led to the discovery of ezetimibe. 

The cholesterol resorption inhibitor ezetimibe, introduced to the market in 2003 as Zetia by the Merck company, works as well as a sequestrant. The compound localises at the brush border of the small intestine and selectively blocks the transport of cholesterol into the circulation and its hver storage. The reduction of the exogenous cholesterol metabolism leads eventually to a drop in LDL cholesterol and a rise in HDL levels. [372]... 

Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, Kato K, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism a randomized controlled trial. EHabetologia 2014 57 878-90. 

Structure of several metabolites, some of which offered advantageous localization to the intestine while others did not [111]. Armed with this knowledge, a second generation compound was designed in which sites of detrimental metabohsm were blocked via strategic incorporation of substituents. The result was ezetimibe (63), a compound which contains hydroxyl functionality crucial to activity and selectivity, as well as fluorine atoms in two key locations which serve to blocked detrimental metabolic pathways without adversely affecting cholesterol absorption inhibitory activity significantly. 

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