Twist and to be square #MedicinalChemistry #memo

MedChem often care about lipophilicity of their own molecule. But it is very important to keep molecular drug like profiles. Spiro cyclic building block and oxetanes are very attractive components for drug discovery.

Following articles are interesting for me.

The first one is letter about azaspiroheptanes and the second one is about oxetane containing molecules. Both articles are published from researchers in AZ. URL is below.

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00248
This article disclosed AZ’s experience of replacement of six membered ring such as piprazines, piperidinez and morphorines to azaspiroheptane. Generally the effect of the replacement rowing lipophilicity and increasing basicity even if the spiroring has more carbon atoms than traditional six membered ring.

The author reported some examples for their MMPA in drug discovery projects. ADMET profiles are improved in most of case however loss potency in some case. Because spiro ring has more straight structure compared to the six membered ring and is twisted 90 degree. It affects molecular conformation, so it changes binding pose of the molecule.

In the conclusion, the author analyzed their experience and give suggestions for the building block usage. It is worth to remember I think.


https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b00030

And the second one is also very interesting article about oxetane ring containing molecule.

In the article the author found that oxetane ring is metabolized by microzomal epoxide hydoraze. This is non CYP metabolic pathway.

So, to introduce the oxetane ring, the molecule has possibility of none CYP metabolic pathway to avoid DDI.

The article disclosed many example of metabolic profiles of oxatane containing molecules. I had interested that molecules that have oxetane ring in terminal position is not unstable and showed good drug clearance.

Medicinal chemistry is exciting!