Do we need measure metabolic stability in chiral form?

Recently the importance of rsp3 ratio is increasing because of accessing designed space, improving physchem properties such as solubility etc.
However, accessibility of chiral compound is difficult due to synthetic accessibility or lack to chiral separation conditions.
As you know, sometime biological activity is quite different between enantiomers. It is as same as ADMET properties. So, how about importance of the chirality in metabolic stability?
Today I found short letter from Merck’s researchers.
“Interpretation of in vitro metabolic stability studies for racemic mixtures”
They analyzed in house DMPK data and conduct simulation. Finally they concluded that the risk of misinforming project teams through generation of metabolic stability data on racemic mixtures is low.

In the Figure 4 of the article shows that frequency of compounds which shows 10 times difference of metabolic stability between R and S enantiomers!

For QSAR modeler it is worth to know the data. BTW, for project member small difference of molecular properties are very important even if the difference is small (2 times). I think drug designer is required balance, to see things from a wide point of view and to see things from a specific view. I need improve myself more and more…


Published by iwatobipen

I'm medicinal chemist in mid size of pharmaceutical company. I love chemoinfo, cording, organic synthesis, my family.

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