An article about strategy for extending half life in vivo

In compound optimization stage, “reduce lipophilicity” is mantra for chemists. High lipophilicity compound tend to be metabolically unstable, promiscuous and binding many off targets. To reduce lipophilicity is important strategy for drug discovery process but it is not always suitable strategy.
Researchers from Genentech report their useful experience in JMC lett.
You can find the article in ASAP, url is below.
https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00047

They analyzed in house in vivo PK data and lipophilicity and summarized that “Decreasing lipophilicity without addressing a metabolic soft-spot will often lead to both lower clearance and volume of distribution without extending half-life”.

You know, reducing lipohilicity is decreasing permeability it is not good for PK. And also Fig2 shows clear cut of their opinion.
In rat PK-IV, it found weak correlation between volume of distribution of unbound fraction (VDss-u) and LogD, clearance of unbound fraction(CLu) and LogD. It means that VDss-u and CLu highly correlates as same as LogD.
And in one component model, half-time is defined as following equation.
T1/2 = VDss,u/CL,u * ln2
From the equation and relation ship between VDss and CL, simple reduction of lipophilicity decreases not only CL,u but also VDss,u and no effect for T1/2!
In the article, the authors analyzed in-house data with MMPA and showed some transformations for improve half-life.
I think it worth to read the article.

MMPA is performed with Knime vernalis node. This tool kit is open source, it can use everybody without fee.
https://www.knime.com/book/vernalis-nodes-for-knime-trusted-extension
MedChem x Chemoinformatics = exciting! ;-)

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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.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01793

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.