Chemistry and Life

Medicinal chemistry. Pharmacology. Toxicology. Environmental sciences.

Why are there so few boron containing drugs?

6 Comments

TavaboroleThe antifungal drug tavaborole was approved by the FDA a few weeks ago. One thing that is unusual about the chemical structure of tavaborole is the boron atom that it contains. Boron is not a common element in pharmaceutical drugs. The cancer drug bortezomib (Velcade) comes to mind, but there aren’t many. The antibiotic compound boromycin contains boron too, but it’s not a marketed drug.

So what’s wrong with boron that prevents its widespread use in pharmaceuticals? As far as I know, and also according to a review in EMBO Reports, there is nothing inherently bad about boron in terms of it being used in medicines. It seems to be that medicinal chemists simply don’t try to use it often.

The company that developed tavaborole, Anacor Pharmaceuticals, is trying to take advantage of this omission. Their whole pipeline of drug candidates are relatively simple organoboron compounds. You can carve out some novel chemical space in terms of intellectual property that way.

I have encountered a similar situation in my career, except instead of an underutilized element, it involved an underutilized functional group. In developing the anticonvulsants JNJ-26990990 and JNJ-26489112, we were able to patent some very simple* compounds because they contained the relatively uncommon sulfamide functional group. We encountered no inherent problems with druggability associated with the sulfamide groups, and noticed that it showed up relatively infrequently in the patent literature, so we came to the conclusion that it was an underappreciated and underutilized functional group in medicinal chemistry.

*Readers in the drug discovery field can imagine how pleased our scale-up group was to learn that our first clinical candidate could be prepared in one step from commercially available materials.

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6 thoughts on “Why are there so few boron containing drugs?

  1. How common is boron in natural product? Does boron show up in nature (organic contexts) very often?

    • Inorganic boron-containing compounds are found in low levels throughout the environment and are essential micronutrients for plants and animals. But in the context of organic chemical compounds, there are few boron-containing natural products. And those that are known don’t have the carbon-boron bonds present in the drugs tavaborole and bortezomib.

  2. That’s interesting. Thanks.

  3. Sulfamide is perfectly fine in a drug as long as the rest of the molecule is greasy. It has the same problem as sulfonamides, only more so – Adding it onto a high polar surface area scaffold (i.e. typical kinase inhibitor with aminopyrimidines, pyridines and the like) would push the inhibitor over the edge, in terms of cell penetration.

    There is a company that uses similarly underutilized dimethylphosphinoxide group, trying to put it everywhere in place of COR, SOR, SO2R. The building block are somewhat expensive to make though – sulfamide is nicer.

    In JNJ-26489112, please have you also looked on the corresponding chromane compounds? – one oxygen less than benzodioxanes. I only ask this because I worked on various chromane series, they are quite lovely to make.

    • Yes, I believe we did make some chromanes, as well as a variety of other oxygen containing heterocycle analogs. They should be covered in WO2007137167 and related patents. Most of what we made were fairly greasy, with BBB penetration being a necessary property, so we didn’t really explore highly polar compounds containing the sulfamide.

  4. I have never seen boron in a drug before until I saw Tolboxane, a tranquilizer.

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