Loratadine analogues as MAGL inhibitors

[Display omitted] Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24μM) and 35-fold higher selectivity over human...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-04, Vol.25 (7), p.1436-1442
Hauptverfasser:	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 J.
Format:	Artikel
Sprache:	eng
Schlagworte:	2-Arachidonoyl glycerol Amidohydrolases - antagonists & inhibitors Amidohydrolases - metabolism Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Fatty acid amide hydrolase Humans Loratadine Loratadine - chemical synthesis Loratadine - chemistry Loratadine - pharmacology Models, Molecular Molecular Structure Monoacylglycerol lipase Monoacylglycerol Lipases - antagonists & inhibitors Monoacylglycerol Lipases - metabolism Recombinant Proteins - metabolism Structure-Activity Relationship α/β hydrolase-6
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Zusammenfassung:	[Display omitted] Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50=1.79μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽10μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.02.037