- Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists
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Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 μM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.
- Tian, Maoqun,Abdelrahman, Aliaa,Baqi, Younis,Fuentes, Eduardo,Azazna, Djamil,Spanier, Claudia,Densborn, Sabrina,Hinz, Sonja,Schmid, Ralf,Müller, Christa E.
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p. 6164 - 6178
(2020/07/10)
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- PHARMACEUTICAL COMPOSITION FOR TREATMENT OF OSTEOARTHRITIS
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A pharmaceutical composition including 2-hydroxy-N—[3-(trifluoromethyl)phenyl]benzamide and used for treatment of osteoarthritis is revealed. The pharmaceutical composition inhibits tumor necrosis factor (TNF) induced interferon regulatory factor (IRF). The activated IRF stimulates chondrocytes to secret matrix metalloproteinases, inducible nitric oxide synthase (iNOS), aggrecanases, etc. This leads to loss of collagen II and further causes degradation of proteoglycan. By suppression of signaling pathways of interferon regulatory factor, symptoms are relieved and osteoarthritis is treated.
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Paragraph 0029; 0030
(2013/03/28)
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- PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE OF SALICYLANILIDES FOR TREATMENT OF HEPATITIS VIRUSES
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A new class of salicylanilides is described. These compounds show strong activity against hepatitis viruses.
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