Christopher Southan, Elena Faccenda, Joanna L. Sharman, Adam J. Pawson, Simon D. Harding, Stephen PH Alexander*, and Jamie A Davies, IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, EH8 9XD, UK. *School of Life Science, University of Nottingham, NG7 2UH UK.

Capturing BIA-10-2474 and related FAAH inhibitor data in the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb)

GtoPdb remit

• Our Wellcome-funded mission is to curate quantitative interactions between human protein targets and their ligands (described in PMID 26464438)

• We surfaced the BIA 10-2474 in our 4th Feb release and our PubChem submission added the name-to-structure mapping into CID 46831476

• While the patent only had % inhibition, in the interests of surfacing important relationships we “bent our rules” by estimating an IC50 and linking to Swiss-Prot O00519

• Our expanded set of FAAH inhibitors is shown below http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1400

Examples of GPCR database tables

Supported by:

Conclusions

• Our extended “information gap filling” lead to SA and CS being quoted in Science, Nature News and Forbes (see

http://www.guidetopharmacology.org/hotTopics.jsp#FAAH• GtoPdb is well positioned to capture and link data, ideally

from new peer-reviewed literature• Insights into mechanistic toxicology (and its avoidance)

urgently need to be independently verified• Logically, this is best expedited by Bial supplying engaging

parties from the stock of BIA 10-2474 made for the trial• The longer it takes to close data gaps the greater the risk

of reputational damage that could reflect across the entire pharmaceutical industry

Extending connections and metadata

Given intense interest in FAAH inhibition , we utilised curators comments, a personal blog and GtoPdb “Hot Topics” to provide ancillary information for the in silico modellers, such as low activity analogues not covered by our database records per se (see diagram below)

Introduction

• BIA 10-2474 is an Fatty Acid Amide Hydrolase (FAAH) inhibitor developed by Bial, Portugal as an analgesic

• On 10th of Jan 2016, during a Phase I trial in Rennes, a male patient in the 50 mg per-day arm was hospitalised, went into a coma and died on the 17th

• Five additional patients in the high dose group were hospitalised

• The trial stop was announced on 15th Jan• Brain MRI showed variable haemorrhagic and necrotic

lesions in the fatality and four of the five• 84 volunteers given lower doses showed no symptoms • Other FAAH inhibitors (e.g. JNJ-42165279 and PF-

04457845) have completed Phase I without issues

Data gaps

• Until the EudraCT protocol was released by ANSM and La Figaro on 24th BIA 10-2474 had only a Bial listing with no structure, no papers and no clinical trial entry

• The protocol specified a structure from a patent • The “Temporary Specialist Scientific Committee”

meeting report of 15 February extrapolates to unlikely in vitro potencies and speculates on irreversibility

• Many questions remain, including animal tox and metabolism results

The primary patent WO2010074588

• Remains the only published source of in vitro data • Has no standardised activity measurements against

purified human FAAH than could be compared • Contains 589 analogues with synthesis descriptions• Potency measurements are limited to patchy %

inhibition data in crude rodent extracts (see the patent Table below with the example 362 inset)

http://www.slideshare.net/cdsouthan/bia-102474-in-gtopdb /capturing-bia102474-and-related-faah-inhibitor-data-inwith slides at: cdsouthan@hotmail.com