55212-32-3Relevant articles and documents
Synthesis and preclinical evaluation of [11C]MA-PB-1 for in?vivo imaging of brain monoacylglycerol lipase (MAGL)
Ahamed, Muneer,Attili, Bala,van Veghel, Daisy,Ooms, Maarten,Berben, Philippe,Celen, Sofie,Koole, Michel,Declercq, Lieven,Savinainen, Juha R.,Laitinen, Jarmo T.,Verbruggen, Alfons,Bormans, Guy
, p. 104 - 113 (2017)
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 [11C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in?vitro inh
Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease
Singh, Yash Pal,Shankar, Gauri,Jahan, Shagufta,Singh, Gourav,Kumar, Navneet,Barik, Atanu,Upadhyay, Prabhat,Singh, Lovejit,Kamble, Kajal,Singh, Gireesh Kumar,Tiwari, Sanjay,Garg, Prabha,Gupta, Sarika,Modi, Gyan
, (2021/09/04)
In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure–activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC50 = 0.96 ± 0.14 μM, BChE IC50 = 1.23 ± 0.23 μM) compared to earlier identified lead molecule EJMC-G (AChE IC50 = 5.74 ± 0.13 μM, BChE IC50 = 14.05 ± 0.10 μM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC50 = 20.25 ± 0.26 μM) over the earlier identified EJMC-B (IC50 = 61.98 ± 0.30 μM) and it also was able to chelate iron. Co-treatment of 13b with H2O2, significantly attenuated and reversed H2O2-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.
A2B Adenosine Receptor Antagonists with Picomolar Potency
Jiang, Jie,Seel, Catharina Julia,Temirak, Ahmed,Namasivayam, Vigneshwaran,Arridu, Antonella,Schabikowski, Jakub,Baqi, Younis,Hinz, Sonja,Hockemeyer, J?rg,Müller, Christa E.
supporting information, p. 4032 - 4055 (2019/05/06)
The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist (Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.
