Latest advances in the discovery of fatty acid amide hydrolase inhibitors

  title={Latest advances in the discovery of fatty acid amide hydrolase inhibitors},
  author={Tiziana Bisogno and Mauro Maccarrone},
  journal={Expert Opinion on Drug Discovery},
  pages={509 - 522}
Introduction: Fatty acid amide hydrolase (FAAH) is the major catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide) that, with different degrees of efficiency, also hydrolyzes other endogenous fatty acid ethanolamides. FAAH is increasingly being considered a relevant therapeutic target, especially in models of inflammatory pain. The opportunity to selectively increase the endocannabinoid tone only in those tissues where such an enhancement can be beneficial might result… 

Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?

This review reports the latest advances in the development of new single targeted and dual-targeted FAAH inhibitors over the past 5 years, which present a new prospect in the pharmaceutical industry for treatment of complex diseases.

Fatty acid amide hydrolase inhibitors: a patent review (2009 – 2014)

FAAH is a promising target for treating many disease conditions including pain, inflammation and mood disorders, and new strategies based on compounds with peculiar in vivo distribution or with multiple pharmacological activities are under investigation and could boost the therapeutic potential of this class in the next future.

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors

Six major cannabis-derived compounds are investigated to compare their action on rat and human FAAHs and it is suggested that the therapeutic efficacy of compounds targeted towards FAAH should be always tested in vitro on bothRat and human enzymes.

Design, microwave‐assisted synthesis, biological evaluation and molecular modeling studies of 4‐phenylthiazoles as potent fatty acid amide hydrolase inhibitors

Several analogs containing structural motifs containing FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies and their inhibition potencies against human FAAH enzyme are evaluated.

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA2α and FAAH, respectively.

Endocannabinoids, Related Compounds and Their Metabolic Routes

The most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system.

Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAh inhibitors, are the topic of this chapter.

Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity.

The piperidine/piperazine urea may represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.

Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide.

  • D. BogerH. Satō B. Cravatt
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide, and anandamide (an endogenous ligand for cannabinoid receptors) is detailed.

Discovery of potent inhibitors of human and mouse fatty acid amide hydrolases.

In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates.

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets

Reversible Inhibitors of Fatty Acid Amide Hydrolase That Promote Analgesia: Evidence for an Unprecedented Combination of Potency and Selectivity

A class of α-keto-heterocycles are identified that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation.

α-Ketoheterocycle-based Inhibitors of Fatty Acid Amide Hydrolase (FAAH).

These efforts defined the impact of the central activating heterocycle and its key substituents, and established the basis for the recent further conformational constraints in the C2 acyl side chain, providing potent, long-acting, orally-active FAAH inhibitors.

Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas.

Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent

Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor.

Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling and is being evaluated in human clinical trials.

Application of computational methods to the design of fatty acid amide hydrolase (FAAH) inhibitors based on a carbamic template structure.