Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

Esbroeck, Annelot C. M. van; Janssen, A. M.; Cognetta, Armand B.; Ogasawara, Daisuke; Shpak, Guy; Kroeg, Mark van der; Kantae, Vasudev; Baggelaar, Marc P.; Vrij, Femke M.S. de; Deng, Hui; Allarà, Marco; Fezza, Filomena; Zhu, Lin; Wel, Tom van der; Soethoudt, Marjolein; Mock, Elliot D.; Dulk, Hans den; Baak, Ilse L.; Florea, Bogdan I.; Hendriks, Giel; Petrocellis, Luciano De; Overkleeft, Herman S.; Hankemeier, Thomas; Zeeuw, Chris I. De; Marzo, Vincenzo Di; Maccarrone, Mauro; Cravatt, Benjamin F.; Kushner, Steven A.; Stelt, Mario van der

doi:10.1126/science.aaf7497

Cited by 270 publications

(235 citation statements)

References 39 publications

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“…However, the nature of this off‐target effect remains obscure, although much speculation has centered around the idea that 8 l is not particularly selective for FAAH. In fact, a recent activity‐based profiling of serine hydrolases revealed that 8 l inhibited not only FAAH, but ABHD6 and some other serine hydrolases, namely FAAH2, CES1, CES2, CES3, ABHD11, LIPE, and PNPLA6, albeit at concentrations several‐fold higher than those needed for FAAH inhibition . Although the published data provide information about the selectivity of 8 l , they do not allow a conclusion about which of the identified off‐targets could be responsible for the observed toxicity.…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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“…[6] This is because this class of chemical matter can also perform many frontier functions that have been minimally utilized to date. These include modulating protein-protein interactions, [7] allosterically modifying protein function, [8] acting as prostheses on the molecular scale, [9] serving as next-generation biological probes, [10] enabling miniaturized diagnostics, [11] harvesting sunlight. [12] transducing energy, [13] emitting light, [14] initiating self-healing, [15] acting as molecular magnets, [16] acting as redox flow batteries, [17] enabling next generation computing, [18] and superconducting.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

2018

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The eighteenth and nineteenth centuries marked a sweeping transition from manual to automated manufacturing on the macroscopic scale. This enabled an unmatched period of human innovation that helped drive the Industrial Revolution. The impact on society was transformative, ultimately yielding substantial improvements in living conditions and lifespan in many parts of the world. During the same time period, the first manual syntheses of organic molecules was achieved. Now, two centuries later, we are poised for an analogous transition from highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of many different types of molecules with the push of a button. Automation of customized small molecule synthesis pathways is already enabling safer, more reproducible, and readily scalable production of specific targets, and general machines now exist for the synthesis of a wide range of different peptides, oligonucleotides, and oligosaccharides. Creating general machines that are similarly capable of making many different types of small molecules on-demand, akin to that which has been achieved on the macroscopic scale with 3D printers, has proven to be substantially more challenging. Yet important progress is being made toward this potentially transformative objective with two complementary approaches: (1) automation of customized synthesis routes to different targets via machines that enable use of many different reactions and starting materials, and (2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these exciting directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.

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“…Shortly thereafter, a report from the US Food and Drug Administration (FDA) concluded that BIA 10‐2474 has a peculiar toxicity profile that does not extend to other FAAH inhibitors. In fact, an in‐depth reinvestigation uncovered a series of off‐target proteins for the same compound …”

Section: Introductionmentioning

confidence: 99%

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

et al. 2018

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The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.

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Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

Cited by 270 publications

References 39 publications

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

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

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

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