Format

Send to

Choose Destination
Br J Pharmacol. 2020 Jan 3. doi: 10.1111/bph.14973. [Epub ahead of print]

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474.

Author information

1
Department of Research, Bial-Portela & Cª., S.A., Coronado (S Mamede & S Romão), Portugal.
2
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.
3
MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.

Abstract

BACKGROUND AND PURPOSE:

In 2016, one person died and four others had mild-to-severe neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474.

EXPERIMENTAL APPROACH:

Pharmacodynamic and pharmacokinetic studies were performed with BIA 10-2474, PF-04457845 and JNJ-42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity-based protein profiling (APBB) in rats. BIA 10-2474 effect in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated.

KEY RESULTS:

BIA 10-2474 was 10-fold less potent than PF-04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED50 values of 13.5 and 6.2 μg·kg-1 , respectively. Plasma and brain BIA 10-2474 levels were consistent with in situ potency and neither BIA 10-2474 nor its metabolites accumulated following repeat administration. FAAH and α/β-hydrolase domain containing 6 were the primary targets of BIA 10-2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen-induced protein 1. At 100 mg·kg-1 for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10-2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.

CONCLUSIONS AND IMPLICATIONS:

BIA 10-2474 potently inhibits FAAH in vivo, similarly to PF-04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off-targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off-targets in the clinical trial accident remains unclear.

PMID:
31901141
DOI:
10.1111/bph.14973

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center