Differences between similar FAAH inhibitors and their in silico target predictions

**UPDATE As of 21st Jan 2016 please note the actual structure of BIA 10-2474 changed to this.

The continuing follow up to the clinical trial disaster.

Chris Southan yesterday suggested I try CID 57880883 as the comparator to CID 54576693 (JNJ-42165279).  These have IC50 75 nM vs 350 nM, respectively according to Jannsen’s WO2011139951. Yesterday I ran predictions for JNJ-42165279 using SEA and SwissTargetPrediction.Today I grabbed the SMILES for CID 57880883 and ran the predictions with results below.

Interestingly the addition of chlorine dramatically changes the predictions with SEA suggesting an interaction with 5HT-2B ranking above FAAH. SwissTargetPrediction does not seem as sensitive producing very similar results to CID 54576693 (clinical trial with this compound cancelled yesterday) at the top of the ranking. Lower down there are differences in targets suggested and ranked.

It would be interesting to see if J&J mentioned issues with 5HT-2B for CID 57880883. Again both compounds have a very different predicted profile to BIA 10-2474. A thorough profiling perhaps across these and other targets is warranted.

Again this underlies perhaps off-target issues and how some molecules in the same class may behave differently – obviously there are structural differences between the Bial compound and the J&J compounds, let alone metabolism differences that should also be considered.

CID 57880883 and SEACID 57880883 and Swiss target predictionimages of molecules

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