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

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 br

SUBMITTER: Bonifacio MJ 

PROVIDER: S-EPMC7161550 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature