Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase

Abstract

Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic-N-carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl- and imidazolyl-N-carboxamide series led to the discovery of clinical candidate 8 l (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide; BIA 10-2474) as a potent and long-acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.

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

“…Fatty acid amide hydrolase activity was determined by measuring the formation of 3 H‐ethanolamine from tritium ( 3 H)‐labelled AEA in Wistar rat brain membranes prepared in house as described elsewhere (Kiss et al, ; Kiss et al, ). The reaction mixture (total volume of 200 μl) contained substrate solution (2 μM of AEA + 5 nM of 3 H‐AEA + 0.1% fatty acid‐free BSA), 10 μg of protein, in fatty acid amide hydrolase incubation buffer (1 mM of EDTA and 10 mM of Tris, pH 7.6) and test compounds (BIA 10‐2474, PF‐04457845 or JNJ‐42165279) ranging from 1 nM to 10 μM.…”

“…BIA 10‐2474 (3‐(1‐(cyclohexyl (methyl)carbamoyl)‐1 H ‐imidazol‐4‐yl)pyridine 1‐oxide; Kiss et al, ), BIA 10‐2445 ( N ‐cyclohexyl‐ N ‐methyl‐4‐(pyridin‐3‐yl)‐1 H ‐imidazole‐1‐carboxamide), BIA 10‐2639 (3‐(1‐(((1 R ,4 R )‐4‐hydroxycyclohexyl)(methyl)carbamoyl)‐1 H ‐imidazol‐4‐yl)pyridine 1‐oxide), and BIA 10‐2631 ( N ‐((1 R ,4 R )‐4‐hydroxycyclohexyl)‐ N ‐methyl‐4‐(pyridin‐3‐yl)‐1 H ‐imidazole‐1‐carboxamide) were synthesized in the Chemistry Department at Bial. PF‐04457845 was obtained from AK Scientific (Union City, CA, USA), and JNJ‐42165279 was obtained from Hangzhou DayangChem (Hangzhou, China).…”

Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development

“…A major clinical trial incident occurred in January 2016, which led to the death of one of the participants during the study with a FAAH inhibitor code-named BIA 10-2474. Following the incident, there has been a solid body of evidence that the drug exhibited an off-target effect. − The tragic results of this trial emphasized that it is especially important to fully understand the pharmacological effects, metabolism, and pharmacokinetic–pharmacodynamic (PK–PD) relationship of drugs in the body before conducting clinical trials. Using PET probes is uniquely well suited for in vivo drug evaluation to assess target engagement and correlate therapeutic dose–target occupancy relationship accurately in humans via a phase 0 study.…”

Pharmacological characterization of a novel, potent, selective, and orally active fatty acid amide hydrolase inhibitor, PKM‐833 [(R)‐N‐(pyridazin‐3‐yl)‐4‐(7‐(trifluoromethyl)chroman‐4‐yl)piperazine‐1‐carboxamide] in rats: Potential for the treatment of inflammatory pain

“…Preclinical studies investigated the role of FAAH using FAAH inhibitors and FAAH knockout mice . Several FAAH inhibitors with brain penetration have been subjected to pharmacological analysis and some of them showed analgesic effects on inflammatory and neuropathic pain without undesirable side effects in rat models . They have reached clinical trials to obtain the proof of concept …”