2021
DOI: 10.1021/acs.jmedchem.1c00076
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Design and Structure–Activity Relationships of Isothiocyanates as Potent and Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibitors

Abstract: N-Acylethanolamines are signaling lipid molecules implicated in pathophysiological conditions associated with inflammation and pain. N-Acylethanolamine acid amidase (NAAA) favorably hydrolyzes lipid palmitoylethanolamide, which plays a key role in the regulation of inflammatory and pain processes. The synthesis and structure-activity relationship studies encompassing the isothiocyanate pharmacophore have produced potent low nanomolar inhibitors for hNAAA, while exhibiting high selectivity (>100-fold) against o… Show more

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Cited by 3 publications
(6 citation statements)
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References 83 publications
(168 reference statements)
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“…We cannot exclude that AM11095 might interfere with morphine pharmacokinetics. AM11095 shows limited interaction with several isoenzymes of cytochromes P450 (CYP) [ 22 ], although it is not known if it interferes with UDP-glucoronosyltransferases, the main metabolizing enzymes of morphine that lead to the formation of the major active metabolite morphine-6-glucuronide. However, we tend to exclude this scenario, as the reduction of microglia and astrocyte activation in the dorsal horn induced by AM11095 when administered with morphine is not fully compatible with the hypothesis of an enhancement of morphine effects by a pharmacokinetic interaction.…”
Section: Discussionmentioning
confidence: 99%
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“…We cannot exclude that AM11095 might interfere with morphine pharmacokinetics. AM11095 shows limited interaction with several isoenzymes of cytochromes P450 (CYP) [ 22 ], although it is not known if it interferes with UDP-glucoronosyltransferases, the main metabolizing enzymes of morphine that lead to the formation of the major active metabolite morphine-6-glucuronide. However, we tend to exclude this scenario, as the reduction of microglia and astrocyte activation in the dorsal horn induced by AM11095 when administered with morphine is not fully compatible with the hypothesis of an enhancement of morphine effects by a pharmacokinetic interaction.…”
Section: Discussionmentioning
confidence: 99%
“…AM11095 was designed and synthesized at the Center for Drug Discovery, Northeastern University, as described in US Patent 9,963,444 B2, 2018 and [ 22 ]. AM11095 is a slowly reversible NAAA inhibitor with a half-maximal inhibitory concentration (IC 50 ) value of 20 nM, while having no effect on serine hydrolases FAAH and MGL activity at concentrations > 10 μM [ 22 ]. A detailed pharmacokinetics analysis of AM11095 (compound 36) in mice is described by Malamas et al [ 22 ].…”
Section: Methodsmentioning
confidence: 99%
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“…Cyclobutyl amino alcohols are versatile synthetic intermediates whose derivatives feature in medicinal chemistry as key components in pharmaceutical candidates, as motifs for exploring QSAR models and in lead/fragment-based drug discovery, and as sp 3 -rich bioisosteric replacements for their aryl counterparts . Despite this, there are few general methods for producing such compounds, particularly in an enantiomerically enriched form.…”
Section: Introductionmentioning
confidence: 99%