A Cyclopropane Amino Acid Bites the Dust

"Ceterum autem censeo,

Carthaginem esse delendam"

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In recent years I have been getting somewhat annoyed with this fear of chirality that is quite widespread in industry and to some extent in academia. Stereogenic centers tend to make synthesis, purification and characterisation more complicated so I can see why it is convenient to avoid it all together and just Sonogashira yourself to death? The compounds that come out of all this tend to be very flat and aromatic and yet industry is puzzled why they aren't getting more new drugs to market. I strongly suspect that there is a very finite number of potential drugs in the flat aromatic category and that we may be getting to the end of the line.

Nature is asymmetric and three-dimensional (nucleosides, amino acids, carbohydrates...etc.) so why are we not devoting more energy to chiral molecules in drug discovery? By now there are many robust and general asymmetric processes and there is the chiral pool (more like a chiral ocean really) so getting into some exciting chiral medchem isn't really that difficult.

Anyway, the reason for this tantrum is the sad news that  Eli Lilly's very cool cyclopropane glutamate analogue LY2140023 has failed phase II trials. This class of compounds has been under way for a long time against a very difficult target and the culmination at Lilly is a densely functionalised beast with 4 contiguous stereocenters. Well CNS is a horrible area to do drug discovery. First time around the drug did really well but this time around placebo was more effective than LY2140023! Hence, Lilly is giving it another shot in clinical trials. Hopefully they will get this sucker back on track. I'd love to see something like this make it all the way. D!