28806-18-0Relevant articles and documents
Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation
Munoz, Lenka,Kavanagh, Madeline E.,Phoa, Athena F.,Heng, Benjamin,Dzamko, Nicolas,Chen, Ew-Jun,Doddareddy, Munikumar Reddy,Guillemin, Gilles J.,Kassiou, Michael
supporting information, p. 29 - 34 (2015/03/30)
LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show antineuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.
The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism
Jain, Harsh V.,Rasheed, Roshni,Kalman, Thomas I.
body text, p. 1648 - 1651 (2010/08/20)
The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.
Kinetics of Electron Transfer from Nitroaromatic Radical Anions in Aqueous solutions. Effects of Temperature and Steric Configuration
Meot-Ner, Michael,Neta, P.
, p. 4648 - 4650 (2007/10/02)
Rate constants for electron transfer from various nitroaromatic radical anions to other nitroaromatic compounds in aqueous solutions have been determined by kinetic spectrophotometric pulse radiolysis.The rate constants were found to increase from ca. 105 to ca. 108 M-1 s-1 upon increase in driving force (ΔE) from 0 to ca. 300mV, while the activation energies decrease from ca. 6 to ca 3 kcal/mol.Nitro compounds with ortho substituents exhibit lower reduction potentials due to rotation of the nitro group away from the ring plane.Anion radicals of such compounds transfer their electrons much more slowly (k down to ca. 106 M-1 s-1) despite the apparent increase in ΔE (to ca. 550 mV).This behavior is rationalized by an increase in solvent reorganization energies around these radical anions caused by localization of the charge.In general, nitroaromatic radical anions donate electrons much more slowly than other radical anions, in reactions with similar driving forces, due to low self-exchange rates for ArNO2/ArNO-..The kinetics show no anomalies in supercooled solutions.
