Friday, April 24, 2009

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!

12 comments:

Ψ*Ψ said...

Hey, now, what do you have against beautiful flat aromatic things and the Sonogashira coupling? :,(

dr.umesh said...

I understand ur concern, but thats part & parcel of research. If we see the history of many drugs there are many due to serendipity. But with so much of technologies developed now a days, we should hope for the best....

milkshake said...

depends what you make. Kinase drugs are meant to be heterocyclic and ugly. You get more room for creativity with protease inhibitors and receptor ligands 9not mentioning antibiotics)

gyg3s said...

Considering the work of Thomas Szasz I'd be curious to know what assay they are using to test the effectiveness of the potential drug.

Daniel Sejer said...

Wow, that is interesting. Thanks for the link to Thomas Szasz. I can actually follow Szasz on some of his points. D!

Daniel Sejer said...

Here's some stuff about Szasz that I copied from Wikipedia:
The myth of mental illness: It is a medical metaphor to describe a behavioral disorder, such as schizophrenia, as an "illness" or "disease". Szasz wrote: "If you talk to God, you are praying; If God talks to you, you have schizophrenia. If the dead talk to you, you are a spiritualist; If you talk to the dead, you are a schizophrenic."[3] While people behave and think in ways that are very disturbing, this does not mean they have a disease. To Szasz, people with mental illness have a "fake disease," and these "scientific categories" are in fact used for power controls. Schizophrenia is "the sacred symbol of psychiatry" and, according to Szasz, is not really an illness. To be a true disease, the entity must somehow be capable of being approached, measured, or tested in scientific fashion. According to Szasz, disease must be found on the autopsy table and meet pathological definition instead of being voted into existence by members of the American Psychiatric Association. Mental illnesses are "like a" disease, argues Szasz, putting mental illness in a semantic metaphorical language arts category. Psychiatry is a pseudo-science that parodies medicine by using medical sounding words invented over the last 100 years. To be clear, heart break and heart attack belong to two completely different categories. Psychiatrists are but "soul doctors", the successors of priests, who deal with the spiritual "problems in living" that have troubled people forever. Psychiatry, through various Mental Health Acts has become the secular state religion according to Thomas Szasz. It is a social control system, which disguises itself under the claims of scientificity. The notion that biological psychiatry is a real science or a genuine branch of medicine has been challenged by other critics as well, such as Michel Foucault in Madness and Civilization (1961).

gyges said...

@Daniel

You may find the following interesting, a link to an interview given by Szasz.

freezedream said...

I guess it's not really surprising that the drug failed owing to the fact that no-one really knows what causes Schizophrenia. No doubt Lilly will be ploughing ahead to re-do the trial with appropriate alterations in order to ensure the data shows a significant difference.

Szasz does indeed make some interesting points on this subject. I don't believe Schizophrenia is a purely physical condition, the symptoms of which can be completely abolished simply by giving a drug or combination of drugs. That's not to say that drugs can't be helpful, though.

However, it would be awesome to see a cyclopropane amino acid as a therapeutic drug. I myself have been working on such compounds for my PhD so it's a bit of a pet interest for me at the moment!

gigio said...

what is the connection to scipio? and what is connection between scipio's bust and a quote from cato the elder? and what is the connection between the quote and what you write?

Daniel Sejer said...

I find myself ranting something along the lines of this post more frequently than I probably should.
Which reminded me of Cato. Allegedly, Cato would finish all his speeches in the senate with "In addition I believe that Carthage should be destroyed" or something to that effect. Scipio Africanus played a prominent role in defeating Hannibal et al. and sacking Carthage.
Yes I know it's pretty far out. D!

DC said...

Daniel - love your site and love your posts. Especially on practical techniques, on ethics, on literature highlights.

Where are you now? Are you very busy? More please :D

Keep up the good work!

Daniel Sejer said...

DC, yes I'm still alive. Snowed under in grant proposals, papers to write, currently writing a chapter for a book. I've got a ton of stuff I want to post about. I think I'll do some posting next week. Glad that someone noticed my absence, D!