Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation

Shang, Yanguo; Hao, Qingjing; Jiang, Kaixuan; He, Mengting

doi:10.1016/j.bmcl.2020.127118

Cited by 17 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ECS comprises of endocannabinoids such as 2-AG and AEA, endocannabinoid receptors, and the corresponding ligands and proteins. Inhibitors of endocannabinoid hydrolases, FAAH and MAGL, are known to have the capacity to increase eCB levels indirectly, causing minimal side effects in comparison to direct supplementation of cannabinoids. − …”

Section: Discussionmentioning

confidence: 99%

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

Bajaj

Zameer

Jain

et al. 2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer's disease is identified by pathological hallmarks such as intracellular neurofibrillary tangles (NFTs) and extracellular amyloid β plaques. Several hypotheses exist to define the neurodegeneration including microglial activation associated with neuroinflammatory processes. Recently, pharmacological inhibition of endocannabinoid (eCB)-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), is being investigated to modulate the pathology of Alzheimer's disease. While MAGL inhibitors upregulate 2-acyl glycerol (2-AG) levels and reduce neuroinflammation, FAAH inhibitors elevate anandamide (AEA) levels and prevent the degradation of HSP-70, thereby preventing the phosphorylation of tau protein and formation of NFTs in neural cells. We investigated the possible neuroprotective potential of the dual MAGL/FAAH inhibitor JZL-195 (20 mg/kg) against ICV-STZ-induced sporadic Alzheimer's disease (SAD) in Swiss albino mice using donepezil (5 mg/kg) as the standard. The protective effects of JZL-195 were observed by the reversal of altered levels of Aβ 1−42 , HSP-70, neuroinflammatory cytokines, and oxidative stress markers. However, JZL-195 expressed no cognitive improvement when assessed by spontaneous alternation behavior and Morris water maze tests and no effects on the AChE enzyme level in the hippocampal tissues of mice. Therefore, the findings of the present study indicate that although JZL-195 exhibited no improvement in cognitive deficits associated with sporadic Alzheimer's disease, it displayed significant reversal of the biochemical anomalies, thereby suggesting its therapeutic potential against the sporadic Alzheimer's disease model.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

Bajaj

Zameer

Jain

et al. 2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…FAAH inhibition or boosting AEA levels inhibits IL-2 ( Rockwell and Kaminski, 2004 ; Kaplan et al, 2005 ; Rockwell et al, 2008 ; Cencioni et al, 2010 ; Patsenker et al, 2015 ; Zajkowska et al, 2020 ), inhibits LIF release ( Maccarrone et al, 2001 ; Maccarrone and Wenger, 2005 ), and reduces MCP-1 levels ( Nakajima et al, 2006 ; Özdemir et al, 2014 ; Rivera et al, 2018 ; Selvaraj et al, 2019 ; Zhang et al, 2020 ; Hermes et al, 2021 ). There are many reports showing that FAAH inhibition or increases in AEA levels reduces TNF levels ( Nakajima et al, 2006 ; Bátkai et al, 2007 ; Naidu et al, 2007 ; Tham et al, 2007 ; Roche et al, 2008 ; Rettori et al, 2012 ; Nader et al, 2014 ; Özdemir et al, 2014 ; Patsenker et al, 2015 ; Petrosino et al, 2018 ; Rivera et al, 2018 ; Selvaraj et al, 2019 ; Shang et al, 2020 ). Following a wide range of inflammatory stimuli, FAAH inhibition or increasing AEA levels also leads to a reduction in IFNγ, IL-1β, IL-6, IL-8, among others ( Nakajima et al, 2006 ; Rettori et al, 2012 ; Özdemir et al, 2014 ; Patsenker et al, 2015 ; Chiurchiù et al, 2016 ; Petrosino et al, 2018 ; Rivera et al, 2018 ; Selvaraj et al, 2019 ; Zhang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Vecchiarelli

Aukema

Hume

et al. 2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Cannabinoids, including cannabis derived phytocannabinoids and endogenous cannabinoids (endocannabinoids), are typically considered anti-inflammatory. One such endocannabinoid is N-arachidonoylethanolamine (anandamide, AEA), which is metabolized by fatty acid amide hydrolase (FAAH). In humans, there is a loss of function single nucleotide polymorphism (SNP) in the FAAH gene (C385A, rs324420), that leads to increases in the levels of AEA. Using a mouse model with this SNP, we investigated how this SNP affects inflammation in a model of inflammatory bowel disease. We administered 2,4,6-trinitrobenzene sulfonic acid (TNBS) intracolonically, to adult male FAAH SNP mice and examined colonic macroscopic tissue damage and myeloperoxidase activity, as well as levels of plasma and amygdalar cytokines and chemokines 3 days after administration, at the peak of colitis. We found that mice possessing the loss of function alleles (AC and AA), displayed no differences in colonic damage or myeloperoxidase activity compared to mice with wild type alleles (CC). In contrast, in plasma, colitis-induced increases in interleukin (IL)-2, leukemia inhibitory factor (LIF), monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF) were reduced in animals with an A allele. A similar pattern was observed in the amygdala for granulocyte colony stimulating factor (G-CSF) and MCP-1. In the amygdala, the mutant A allele led to lower levels of IL-1α, IL-9, macrophage inflammatory protein (MIP)-1β, and MIP-2 independent of colitis—providing additional understanding of how FAAH may serve as a regulator of inflammatory responses in the brain. Together, these data provide insights into how FAAH regulates inflammatory processes in disease.

show abstract

“…Recently Shang and coworkers identified a carbohydrazone compound 3 (IC 50 = 2.8 μm) as a selective FAAH inhibitor. [26] They reported that the carbohydrazone core formed a tetrahedral intermediate with a catalytic triad (Ser241) and oxyanion hole (Ile238 and Gly239) and is essential for inhibitory activity. Their results revealed that incorporation of a hydrophobic moiety at the N-terminal of carbohydrazone led to selectivity towards FAAH.…”

Section: Figure 2 Design Of New Isatin-based Carbohydrazones As Dual Faah-magl Inhibitorsmentioning

confidence: 99%

Discovery of Isatin‐Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

Jaiswal

Ayyannan

2021

ChemMedChem

View full text Add to dashboard Cite

Using ligand-based design strategy, a set of isatin-3-carbohydrazones was designed, synthesized and evaluated for dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition properties. Compound 5-chloro-N'-(5-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 b) emerged as a potent MAGL inhibitor with nanomolar activity (IC 50 = 3.33 nM), while compound 5-chloro-N'-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 j) was the most potent selective FAAH inhibitor (IC 50 = 37 nM). Compound 5-chloro-N'-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 c) showed dual FAAH-MAGL inhibitory activity with an IC 50 of 31 and 29 nM respectively. Enzyme kinetics studies revealed that the isatin-based carbohydrazones are reversible inhibitors for both FAAH and MAGL. Further, blood-brain permeability assay confirmed that the lead compounds (13 b, 13 c, 13 g, 13 m and 13 q) are suitable as CNS candidates. Molecular dynamics simulation studies revealed the putative binding modes and key interactions of lead inhibitors within the enzyme active sites. The lead dual FAAH-MAGL inhibitor 13 c showed significant antioxidant activity and neuroprotection in the cell-based cytotoxicity assay. In summary, the study yielded three potent FAAH/MAGL inhibitor compounds (13 b, 13 c and 13 j) with acceptable pharmacokinetic profile and thus can be considered as promising candidates for treating neurological and mood disorders.

show abstract

Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation

Cited by 17 publications

References 23 publications

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Discovery of Isatin‐Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

Contact Info

Product

Resources

About