27 February 2011

Not all aromatics stink the same

A couple years ago we highlighted research suggesting that the more aromatic rings in a molecule, the less “developable” it is likely to be. In the February issue of Drug Discovery Today, the same researchers have now published an update in which they dig into the data in more depth and find that not all aromatic rings are created equal.

As before, the researchers turned to the GlaxoSmithKline internal database of tens of thousands of compounds to correlate chemical features with a variety of measured properties that have an impact on drug development, including solubility, logD, human serum albumin binding, inhibition of several cytochrome P450 isozymes, and hERG inhibition. What they found is summarized in the figure:

In short, while an increase in the number of all-carbon aromatic rings (carboaromatics) had a serious negative effect on nearly all parameters, an increase in the number of heteroaromatic rings was much less problematic. All-carbon aliphatic rings were relatively benign (albeit also relatively rare), while heteroaliphatic rings actually improved most of the properties with the exception of hERG inhibition (and this was only a problem with charged molecules).

One point that was unaddressed in the previous paper was whether an increasing number of aromatic rings is problematic in and of itself, or if this is merely a proxy for larger molecules. In this paper, the authors probed this question directly by examining the properties of molecules with similar molecular weights and lipophilicities but different numbers of aromatic rings. Significantly, the deleterious effects of aromatics appear relatively independent of both size and lipophilicity.

The authors also analyzed ring counts in 1200 oral drugs and found that, while the number of carboaromatic and aliphatic rings has remained relatively constant over time, the number of heteroaromatic rings has roughly doubled from the 1960s to today.

These results provide more support for making sure that fragment libraries contain a good assortment of aliphatics - particularly heteroaliphatics. Aromatics are still very useful of course: as the researchers note, there are thousands of commercially available aromatics, many robust chemistries exist for modifying them, and aromatics provide rigid scaffolds. Thus, fragment libraries should still include a fair share of these moieties, but it is probably worth cutting the number of carboaromatics in favor of more heteroaromatics.

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