Not So Boring:  Boron-Containing Antibiotics Create a Stir

Why are there so few boron-containing drugs on the market?  The cancer drug bortezumib (Velcade®) may be the only better-known drug on the market with a boron atom in its structure.[1]  Among antibiotics, there is Kerydin™ (tavaborole), an approved topical solution for the treatment of onychomycosis caused by Trichophyton but no systemically administered drugs containing the metalloid boron.

This may be changing soon. Indeed, several IV and oral boron-containing compounds are undergoing clinical trials.  Many of them were originally developed by Anacor Pharmaceuticals, a company specializing in boron chemistry[2].

  • Originally an Anacor drug, SCYX-7158, an oral oxaborole compound is now being developed by Scynexis for African trypanosomiasis.[3]  A Phase 1 study has been completed some time ago but results are not yet in the public domain.[4]
  • The failure of the GSK2251052 (aka AN3365), a benzoxaborole, in Phase 2 – of all things, in a cUTI study! – came as a surprise. This leucyl tRNA synthase inhibitor, inlicensed from Anacor, had all the trappings of a great broad-spectrum antibiotic.  MIC90s showed impressive activity (usually ≤1 mg/L) against gram-negative bacteria, including MDR strains. Hence, when GSK decided to discontinue further work on the compound because of ‘microbiological findings” it sounded somewhat unbelievable, if not paradoxical [5] [6] [7].
    Well, it was true: ‘emergence of resistance’ during therapy prompted GSK to stop all studies and return the compound to Anacor. Hopefully, some sharp research fellow will study this phenomenon and tell us why in-vitro and in-animal data did not hold up in-homine.
  • Rempex RPX7009, a novel BLI is being developed as carbavance in Novel -lactamase inhibitors: a therapeutic hope against the scoucombination with an unspecified penem by The Medicines Company. This is a non-betalactam BLI which confers protection against Class A BLs. It does not inactivate Class B (MBLs) or Class D (OXA-type) enzymes. It is devoid of intrinsic antibacterial activity. A Phase 1 SAD and MAD study were completed in 2013; however, safety/tolerability data have not yet been published.

In summary, boron-containing compounds have made it into the clinic. So far, there are no reports of safety issues but published data are sparse. The demise of GSK ‘052 was due to problems with efficacy, not safety. Theoretical concerns about the reactivity of boron causing side effects remain for now…well, just theoretical.

Abbreviations:

BL/BLI                betalactamase / betalactamase-inhibitor
MBL                      Metallo-betalactamase
SAD, MAD            single/multiple ascending dose
cUTI                      complicated urinary tract infection

References:
[1] http://pipeline.corante.com/archives/2012/03/05/trouble_with_a_boroncontaining_drug_candidate.php
[2] B. Sekhon. Res Pharm Sci. 2013 Jul-Sep; 8(3): 145–158
[3] S. Wring. Parasitology. Jan 2014
[4] http://www.scynexis.com/pipeline/scyx-7158/
[5] R. Mendes.  AAC. 2013, 57(6):2849
[6] See Anacor webside http://www.anacor.com/gsk052.php
[7] http://www.clinicaltrials.gov/ct2/show/results/NCT01381549?term=gsk2251052&rank=5

 

Print Friendly, PDF & Email

Leave a Reply

Your email address will not be published.