Memo from ACS medicinal chemistry letters #memo #journal

Recently I spend most of my working time at my desk because I’m member of chemoinformatics team. When I worked at bench as a chemist, I often used not only LCMS but also TLC for checking reaction progress. UV lump is common tool for visualizing spot if reagents has uv reactive substituents such as phenyl ring. But if compounds have no such kinds of substituents, I used coloration reagents such as anisaldehyde, Phosphomolybdic Acid, Ninhidorin etc. It was interesting for me to find suitable coloration reagents for compounds which don’t show UV.

Today I read interesting article which could find ACS JMC Lett. Here is the link. This article is freely accessible ;)

The target is arginase which converts arginine to ornitine and the target is cancer. The interesting point for me is that first compound ABH ((S)-2-amino-6-boronohexanoic acid) seems too small, very polar and no aromatic rings. ABH has no ring, so the author tried to add ring to fix the compound conformation. And it worked very well so they could get high LE compound.

After that, they modified cyclized proline derivative 4a and finally found 27 which has good enzyme potency and rodent bioavailability.

All compounds which are described in the article has low molecular weight (~300) and polar properties. Due to the polarity all compounds showed low cell potency because of low permeability however the target is located extra cellar so low permeability will not matter.

The design is based on X-ray. structure based drug design and all compounds has low molecular weight, high polarity. I thought it’s difficult to detect reaction progress with TLC however they explored SAR and optimeze compound. Suitable compound profile should be defined by target not traditional rule such as Ro5. It’s worth to remember I think.


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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