Identification and Characterization of Carprofen as a Multitarget Fatty Acid Amide Hydrolase/Cyclooxygenase Inhibitor

Favia, Angelo D.; Habrant, Damien; Scarpelli, Rita; Migliore, Marco; Albani, Clara; Bertozzi, Sine Mandrup; Dionisi, Mauro; Tarozzo, Glauco; Piomelli, Daniele; Cavalli, Andrea; Vivo, Marco De

doi:10.1021/jm3011146

Cited by 74 publications

(79 citation statements)

References 59 publications

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“…FAAH showed no preference for either enantiomer, with each being more active than the racemate 10r . By contrast, in analogy to prior studies on different classes of FAAH/COX inhibitors, [30, 33] substantial differences were observed on COX-1 and COX-2. Compound (+)- 10r was highly potent on both COX-1 (IC 50 =0.29 nM) and COX-2 (IC 50 =50 nM), whereas (−)- 10r was weakly active on either target.…”

Section: Resultssupporting

confidence: 52%

“…In addition to its high balanced potency, the highest reported thus far, [27, 28, 30, 32, 33, 65] we found that 10r displays no off-target activities on a panel of >90 biologically relevant targets, and effectively engages its intended targets after oral administration in mice. [51]…”

Section: Resultsmentioning

confidence: 79%

“…Nevertheless, these initial results encouraged us because 10a was one of the most potent FAAH/COX-1 inhibitors previously reported. [27, 28, 30, 32, 33, 65]…”

Section: Resultsmentioning

confidence: 99%

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Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Migliore

Habrant

Sasso

et al. 2016

European Journal of Medicinal Chemistry

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Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multi-target FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 79%

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Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Migliore

Habrant

Sasso

et al. 2016

European Journal of Medicinal Chemistry

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“…In conclusion, the development of dual FAAH-COX inhibitors would be of great potential value as a therapeutic strategy to treat different types of pain. Indeed, efforts are underway to synthesize such compounds (Favia, Habrant et al 2012; Cipriano, Bjorklund et al 2013). …”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models

Grim

Ghosh

Hsu

et al. 2014

Pharmacology Biochemistry and Behavior

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Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent preclinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinociceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FAAH inhibitor PF-3845 in models of neuropathic pain (i.e., chronic constrictive injury of the sciatic nerve (CCI)) and inflammatory pain induced by an intraplantar injection of carrageenan. Here, we report that combined administration of subthreshold doses of these drugs produced enhanced antinociceptive effects in CCI and carrageenan pain models, the latter of which was demonstrated to require both CB1 and CB2 receptors. The combined administration of subthreshold doses of these drugs also increased AEA levels and decreased prostaglandin levels in whole brain. Together, these data add to the growing research that dual blockade of FAAH and COX represents a potential therapeutic strategy for the treatment of neuropathic and inflammatory pain states.

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“…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.

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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.

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Identification and Characterization of Carprofen as a Multitarget Fatty Acid Amide Hydrolase/Cyclooxygenase Inhibitor

Cited by 74 publications

References 59 publications

Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models

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

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