A Binding Site for Nonsteroidal Anti-inflammatory Drugs in Fatty Acid Amide Hydrolase

Bertolacci, Laura; Romeo, Elisa; Veronesi, Marina; Magotti, Paola; Albani, Clara; Dionisi, Mauro; Lambruschini, Chiara; Scarpelli, Rita; Cavalli, Andrea; Vivo, Marco De; Piomelli, Daniele; Garau, Gianpiero

doi:10.1021/ja308733u

Cited by 53 publications

(59 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast mavacoxib is COX-2 selective, a characteristic of the coxib class of NSAIDs. Meloxicam, although not a coxib, is also considered to be relatively COX-2 selective [45].…”

Section: Discussionmentioning

confidence: 99%

The long-acting COX-2 inhibitor mavacoxib (Trocoxil¿) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells

et al. 2014

View full text Add to dashboard Cite

Background: The NSAID mavacoxib (Trocoxcil™) is a recently described selective COX-2 inhibitor used for the management of inflammatory disease in dogs. It has a long plasma half-life, requiring less frequent dosing and supporting increased owner compliance in treating their dogs. Although the use of NSAIDs has been described in cancer treatment in dogs, there are no studies to date that have examined the utility of mavacoxib specifically. Results: In this study we compared the in vitro activity of a short-acting non-selective COX inhibitor (carprofen) with mavacoxib, on cancer cell and cancer stem cell survival. We demonstrate that mavacoxib has a direct cell killing effect on cancer cells, increases apoptosis in cancer cells in a manner that may be independent of caspase activity, and has an inhibitory effect on cell migration. Importantly, we demonstrate that cancer stem cells derived from osteosarcoma cell lines are sensitive to the cytotoxic effect of mavacoxib.

show abstract

“…In contrast mavacoxib is COX-2 selective, a characteristic of the coxib class of NSAIDs. Meloxicam, although not a coxib, is also considered to be relatively COX-2 selective [45].…”

Section: Discussionmentioning

confidence: 99%

The long-acting COX-2 inhibitor mavacoxib (Trocoxil¿) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[20] Therefore, FAAH has been proposed as a relevant therapeutic target for the treatment of pain and central nervous system (CNS) disorders. [21][22][23][24][25] Recently, we identified and synthetized a soluble fluorinated substrate analogue (ARN1203) [12] of AEA. Using ARN1203, we successfully performed n-FABS against FAAH resulting in the identification of inhibitors with novel chemical scaffolds.…”

mentioning

confidence: 99%

Fluorine NMR‐Based Screening on Cell Membrane Extracts

Veronesi¹,

Romeo²,

Lambruschini³

et al. 2013

ChemMedChem

Self Cite

View full text Add to dashboard Cite

The possibility of measuring the action of inhibitors of specific enzymatic reactions in intact cells, cell lysates or membrane preparations represents a major advance in the lead discovery process. Despite the relevance of assaying in physiological conditions, only a small number of biophysical techniques, often requiring complex set‐up, are applicable to these sample types. Here, we demonstrate the first application of n‐fluorine atoms for biochemical screening (n‐FABS), a homogeneous and versatile assay based on 19F NMR spectroscopy, to the detection of high‐ and low‐affinity inhibitors of a membrane enzyme in cell extracts and determination of their IC50 values. Our approach can allow the discovery of novel binding fragments against targets known to be difficult to purify or where membrane‐association is required for activity. These results pave the way for future applications of the methodology to these relevant and complex biological systems.

show abstract

“…Additionally, benzothiazole, 29 b-lactam, 30 (thio)hydantoins 31 and some nonsteroidal anti-inammatory drugs (NSAIDs) [32][33][34] also have been reported to inhibit FAAH. Although the overall physiological role of FAAH has been reported, it is difficult to distinguish the function of FAAH in each specic tissue and organ.…”

Section: 28mentioning

confidence: 99%

Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors

Qiu

Ren

et al. 2017

RSC Adv.

View full text Add to dashboard Cite

Fatty acid amide hydrolase (FAAH) is one of the key enzymes involved in the biological degradation of endocannabinoids, especially anandamide. Pharmacological blockage of FAAH restores the levels of endocannabinoids, providing therapeutic benefits in the management of inflammation, depression and multiple sclerosis. In this study, a series of uracil urea derivatives as FAAH inhibitors were designed and synthesized. Structural modifications at the C5 position and side chain of N-hexyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-carboxamide (1a) led to FAAH inhibitors with improved potency and selectivity.Structure-activity relationship (SAR) studies indicated that C5 electron-withdrawing substituents were preferred for optimal potency but not for selectivity, whereas replacement of the alkyl chain with phenylalkyl moieties or biphenyl groups significantly improved both inhibitory potency and selectivity towards FAAH. Two highly potent picomolar FAAH inhibitors (4c, IC 50 ¼ 0.3 AE 0.05 nM; 4d, IC 50 ¼ 0.8 AE 0.1 nM) were developed. Compound 4c inhibited FAAH in a rapid, selective, noncompetitive, and irreversible pattern. This study provides several highly potent and selective FAAH inhibitors and an optimized chemical scaffold for the development of FAAH inhibitors. We anticipate that these FAAH inhibitors will enable new possibilities in understanding FAAH functions and development of therapeutics for pain and inflammatory diseases.

show abstract

A Binding Site for Nonsteroidal Anti-inflammatory Drugs in Fatty Acid Amide Hydrolase

Cited by 53 publications

References 43 publications

The long-acting COX-2 inhibitor mavacoxib (Trocoxil¿) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells

The long-acting COX-2 inhibitor mavacoxib (Trocoxil¿) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells

Fluorine NMR‐Based Screening on Cell Membrane Extracts

Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors

Contact Info

Product

Resources

About