Loratadine analogues as MAGL inhibitors

Patel, Jayendra Z.; Ahenkorah, Stephen; Vaara, Miia; Staszewski, Marek; Adams, Yahaya; Laitinen, Tuomo; Navia-Paldanius, Dina; Parkkari, Teija; Savinainen, Juha R.; Walczyński, Krzysztof; Laitinen, Jarmo T.; Nevalainen, Tapio

doi:10.1016/j.bmcl.2015.02.037

Cited by 24 publications

(21 citation statements)

References 49 publications

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“…Indeed, previous studies have shown that MAGL blockade has several beneficial outcomes in inflammation, pain, anxiety, neurodegeneration and cancer [10,[12][13][14][15]. In the recent past, a number of selective and potent MAGL inhibitors have been developed to modulate MAGL activity [16][17][18][19][20]. Cravatt et al identified some interesting carbamate containing small molecule inhibitors of MAGL, particularly JW-642 was reported to have an IC 50 value of 3.7 nM for hMAGL [16].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Ahamed

Attili

Veghel

et al. 2017

European Journal of Medicinal Chemistry

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MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in vitro inhibitory activity, ex vivo distribution, brain kinetics and specificity of [C]MA-PB-1 binding were studied. Ex vivo biodistribution and microPET showed good brain uptake which could be blocked by pretreatment with both MA-PB-1 and a structurally non-related MAGL inhibitor MJN110. These initial results suggest that [C]MA-PB-1 is a suitable tracer for in vivo imaging of MAGL.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Ahamed

Attili

Veghel

et al. 2017

European Journal of Medicinal Chemistry

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“…As a novel dual-action agent, compound 149 is desirable to be profiled in a model of inflammation. 154 45…”

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Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

et al. 2016

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“…Known carbamate inhibitors of FAAH inhibit the enzyme by covalent carbamoylation of the active site serine . To investigate whether our new carbamate compounds also affected the enzyme in such a manner, the reversibility of enzyme inhibition by phenyl carbamate 46 and pyridin‐3‐yl carbamate 59 was studied following a published procedure . The enzyme preparation was pre‐incubated with these inhibitors at concentrations ranging from approximately 0.1‐ to 10‐fold their IC 50 value.…”

Section: Resultsmentioning

confidence: 99%

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

et al. 2016

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Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(ω-imidazolyl- and ω-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts.

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Loratadine analogues as MAGL inhibitors

Cited by 24 publications

References 49 publications

Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

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