Discovery of Novel 2,5-Dioxoimidazolidine-Based P2X₇Receptor Antagonists as Constrained Analogues of KN62

Abstract

Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.

Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production

“…1D). Interestingly, ATP-induced [Ca 2+ ]i increases were potently suppressed by KN62, a selective P2X7 antagonist 21 , in TAMR-MCF-7 cells, but not in MCF-7 cells. The results demonstrate that P2X7 plays a major role in ATP-dependent calcium signaling only in TAMR-MCF-7 cells.…”

Ionotropic P2X ATP Receptor Channels Mediate Purinergic Signaling in Mouse Odontoblasts

“…BzATP (300 μM), which is P2X 7 receptor selective agonist (Salas et al, 2013; Shieh et al, 2014), evoked current with a peak value of 26.4 ± 1.1 pA/pF ( N = 3; Figures 3C,E). In addition, BzATP-induced inward currents were inhibited by P2X 7 receptor antagonist, 10 nM KN62 (Park et al, 2015), to the amplitudes of 5.0 ± 1.6 pA/pF ( N = 3; Figures 3D,E). BzATP elicited inward currents in a concentration dependent manner ( N = 3, Figure 3F).…”

Synthesis, Biological Activity and Molecular Docking Studies of Novel Sulfonate Derivatives Bearing Salicylaldehyde

“…Aryl sulfonate ester linkages frequently exist in various natural products [1] . The bioactive properties of these compounds have made them interesting targets for chemists [2–8] . Recently, the synthesis, characterization, and antidiabetic potentials of novel aryl sulfonyloxy‐5‐arylidene thiazolidine‐2,4‐dione analogs were evaluated by Mehta and Mahapatra [9] .…”