Publications by authors named "Katie De Wagter"

To reduce the drug attrition due to failure in clinical trials, an early accurate hepatic clearance (CL) prediction for small molecule drugs is critical. However, the routinely used in vitro to in vivo extrapolation (IVIVE) methods to predict human CL have led to significant underpredictions for many drug discovery programs. The ex vivo isolated perfused rat liver (IPRL) can be employed as a model to gain a mechanistic understanding of the root cause(s) of the frequent suboptimal performance of IVIVE methods.

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A LC/MS method using atmospheric pressure chemical ionization, positive ion mode and full scan to measure the in vitro metabolic stability of cyanoalkyl functionalized compounds with the human liver microsomes was employed. Percentage metabolism examined for the five cyanoalkyl piperidines revealed the optimal chain length and positioning of these functions to produce the most metabolically stable compound. The 4-cyanomethyl piperidine derivative was the most stable compound with 15% metabolism after 15 min incubation with human liver microsomes.

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