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

Autores da FMUP

• Patrício Manuel Vieira Araújo Soares Da Silva

  Autor

Participantes de fora da FMUP

• Bonifácio, MJ
• Sousa, F
• Aires, C
• Loureiro, AI
• Fernandes-Lopes, C
• Pires, NM
• Palma, PN
• Moser, P

Unidades de investigação

• Biomedicina

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 mu g center dot 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 alpha/beta-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 center dot 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.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Keywords

• 3 [1 [cyclohexyl(methyl)carbamoyl] 1h imidazol 4 yl]pyridine 1 oxide; amide; arachidonic acid; fatty acid; hydrolase; n (3 pyridazinyl) 4 [3 (5 trifluoromethyl 2 pyridinyloxy)benzylidene] 1 piperidinecarboxamide; n (4 chloro 3 pyridinyl) 4 [(2,2 difluoro 1,3 benzodioxol 5 yl)methyl] 1 piperazinecarboxamide; animal cell; animal experiment; animal model; animal tissue; Article; controlled study; CV-1 cell line; drug blood level; drug mechanism; drug potency; ED50; enzyme activity; essential hypertension; ex vivo study; human; IC50; in vitro study; in vivo study; lipid fingerprinting; male; mouse; nonhuman; priority journal; protein domain; rat