2327-45-9Relevant articles and documents
Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors
Granchi, Carlotta,Bononi, Giulia,Ferrisi, Rebecca,Gori, Eleonora,Mantini, Giulia,Glasmacher, Sandra,Poli, Giulio,Palazzolo, Stefano,Caligiuri, Isabella,Rizzolio, Flavio,Canzonieri, Vincenzo,Perin, Tiziana,Gertsch, Jürg,Sodi, Andrea,Giovannetti, Elisa,Macchia, Marco,Minutolo, Filippo,Tuccinardi, Tiziano,Chicca, Andrea
, (2020/10/14)
An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.
BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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Page/Page column 563, (2018/03/25)
Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
Concise Synthesis of Dictyoquinazol A via a Dimerisation-Cyclocondensation Sequence
Wangsahardja, Jonatan,Marcolin, Gabriella M.,Lizarme, Yuvixza,Morris, Jonathan C.,Hunter, Luke
supporting information, p. 1237 - 1240 (2016/05/10)
A two-step total synthesis of the neuroprotective alkaloid, dictyoquinazol A, has been achieved. The brevity of this synthesis was enabled by exploiting the hidden symmetry of the target molecule. Several structural analogues were also prepared using a similar strategy. These results provide a platform for future structure-activity relationship studies in the quest for a novel treatment for stroke.
