An article about PDE2a Inhibitors

I read an article on my way to work in this morning. It was very exciting article for me.
A story about PDE2a inhibitors.

PDE2a is one of Phosphodiesterase family and be interested in PDE inhibitors for the treatment of CNS disorders.
In the article, the SAR started from HTS hit 3. They got co-crystal structure of compound 7 and the structure indicated that intramolecular hydrogen bonding between amide NH and core scaffold. In consequence the molecule has U shaped conformation. At first, I thought the U shape is key for activity, so it’s difficult to remove amide bond.
But …. It was a mistake! They changed modified around amide bond of compound 9. And it improved potency dramatically! It was interesting for me that conformation of compound 7 and 9 is almost same, even if compound 9 does not have amide NH.(Fig1)

They discussed energy conformation relationship between 7 and 9(Fig4)T. he lowest conformation is bound-sate. I want to know that which do first calculation or synthesis. 😉
Next step the optimized permeability focused on piperidine ring. They introduced fluorine atom on the ring and improved PAMPA-BBB. Lilting SAR♪
Finally they carefully optimized right part and got compound 27 with good PK profile. The compound showed efficiency in vivo model.

The article is not so long, but very impressive for me.



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