Hot topic: (but in this case, stale beer) the long overdue primary pharmacological characterisation of BIA 10-2747

The unfortunate French clinical trial disaster in which the FAAH inhibitor BIA 10-2747 (ligand ID 9001)  left one participant dead and several others with serious neurological adverse events, occurred back in January 2016.  However, the primary publication that describes the properties of this lead compound from its Portuguese originators BIAL has only now appeared in September of 2018 (1).  It is more typical for pharmaceutical medicinal chemistry teams to report their initial in vitro optimisation of a clinical candidate well in advance of Phase 1 (i.e. we might have expected to see this paper circa 2017).  While much has been written about 10-2747 in the last two years, very little peer-reviewed data has appeared (see this slide set and blog post).  In this context, the only BIAL journal paper so far on this compound is a disappointment.  The SAR of the series is only reported as % inhibition determinations rather than the more standardised and usefully comparative IC50s (this means we would actually not curate interaction data from such a paper but we have added the reference to the ligand entry). In addition, they do not address experimentally the irreversibility topic over which there has been some confusion. We would also quibble with the use of  “potent” in the title since an independent report of the initial IC50 binding  (i.e. without pre-incubation for inactivation) was only 7.5 uM (2).

Comments by Chris Southan (@cdsouthan)

1. Kiss et al  (2018). Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.  ChemMedChem, [Epub ahead of print]. [PMID:30113139].
2. van Esbroeck et al. (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 Science, 356(6342):1084-1087 (PMID: 28596366)