1. milkshake on March 24, 2010 11:48 AM writes...

the privileged scaffold concept is oversold by people who do combichem/parallel synthesis stuff and of course want to maximize the "drug-likeness' of what they are making.

I think the 'privileged scaffold" makes sense in CNS where you want to have a molecule that is already optimized to get into brain and has the right size, shape and grease/polar area to bind
to receptors there. Typically one sees pharmacologically-rich profile with such class, which is a good or bad thing.

Another example is aminopyrimidines and aminopyridines and also Sutent-like oxindoles, which are universal -enough that they could be elaborated to inhibit almost every know kinase. The problem there is that such elaboration is often done at cost of intolerably enlarging the molecule size and number of polar groups - which then ruins the drug properties.

2. RB Woodweird on March 24, 2010 11:52 AM writes...

If a scaffold is "privileged" because it appears as a template in more than one endogenous ligand, then isn't building a drug on that template an invitation to cross-reactivity? Shouldn't the ultimate silver bullets be built on scaffolds the nontarget receptor systems have absolutely no interest in?

3. Anonymous on March 24, 2010 1:49 PM writes...

fyi, the latest issue of Nature has a story on the Sirtris controversy. it cites (indirectly) some of the reporting on this blog.

http://www.nature.com/news/2010/100324/full/464480a.html

4. anchor on March 24, 2010 2:44 PM writes...

#2 : Well said but your right and wrong. Understand that you need a quick platform to study the biology, efficacy and other things, if your company is initiating a therapeutic area. Prior scaffold can be helpful in this regard. As for off-target activity, it can be dialed out. I think "priviliged", scaffold design can serve the purpose well and working in parallel, If you come out with a new lead, then you have a head start.

5. Pat Pending on March 24, 2010 3:22 PM writes...

You may have problems finding freedom-to -operate and patentable space within a generic "privileged scaffold" molecular space.

6. Medchem23 on March 25, 2010 3:09 AM writes...

This fits in the same category as LE and various other med chem dogmas. Basically people trying to carve a little niche for themselves by hyping up a bit of pseudo science.

7. chris on March 25, 2010 3:39 AM writes...

Klaus Mueller gave an interesting talk at the 2009 Cambridge Medchem meeting in which he described their work to define the requirements for a "privileged structure", "Small, non-planer structures with robust conformations that provide interesting 3D exit vectors for substitution, with drug-like properties and ideally readily accessible synthetically. He talked mainly about 7-membered rings in which restraints (annulated rings, amides etc) gave clearly defined structures which he illustrated by small molecule and docked ligand crystal structures.

8. UK Chemist on March 25, 2010 4:12 AM writes...

Privileged can also mean'we can't be bothered to think of anything esle'

9. UK Chemist on March 25, 2010 4:18 AM writes...

Privileged can also be med chem code for'we can't be bothered to make anything else'.

10. SPRITY on March 25, 2010 9:20 AM writes...

All the privileged scaffold publications or presentations are simply a reflection of the problem that we do not know where the chemical space overlap with the biological space. The problem was demonstrated in the early days of the combichem era. With a few exceptions in which one could design biologically active molecules based on structure or mechanistic insights, such as kinases and proteases, it is extremely difficult to come up with a hit. Small pharma or academic lab do not have access to large number of biologically active compounds collected through decades of med chem projects. The logical thing to do is to start in the known biological space. The whole purpose of the privileged scaffold library is to find a hit or tool compound as a starting point. One can deal with the selectivity or freedom-to-operate issues after demonstrating that the biological target is disease relevant. Med chem projects are always full of surprise. A novel hit does not guarantee that it is free of cross-activity. CYPs are not very picky enzymes after all.

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