- Design, Synthesis, and Biological Activity of New N -(Phenylmethyl)-benzoxazol-2-thiones as Macrophage Migration Inhibitory Factor (MIF) Antagonists: Efficacies in Experimental Pulmonary Hypertension
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Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats.
- Le Hiress, Morane,Akagah, Bernardin,Bernadat, Guillaume,Tu, Ly,Thuillet, Rapha?l,Huertas, Alice,Phan, Carole,Fadel, Elie,Simonneau, Gérald,Humbert, Marc,Jalce, Ga?l,Guignabert, Christophe
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p. 2725 - 2736
(2018/04/23)
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- N-benzyl-benzoxazolone compound and synthesis method thereof
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The invention provides an N-benzyl-benzoxazolone compound and a synthesis method thereof. Under the condition of sealed air, catalyzed without metal, a benzoxazolone compound directly reacts with a methylbenzene compound to prepare the N-benzyl-benzoxazolone compound. Compared with the prior art, the synthesis method is very simple and convenient, raw materials are easy to obtain, the cost is low, the efficiency is high, the method is suitable for various reaction substrates. Prepared products can be used for clinical drugs and drug intermediates capable of effectively treating diseases.
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Paragraph 0087-0092
(2017/10/07)
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- Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)
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The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto-enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1 μM hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC50 values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF-CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.
- Hare, Alissa A.,Leng, Lin,Gandavadi, Sunilkumar,Du, Xin,Cournia, Zoe,Bucala, Richard,Jorgensen, William L.
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scheme or table
p. 5811 - 5814
(2010/12/20)
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- MIF MODULATORS
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The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression
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Page/Page column 33
(2010/04/03)
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- Anti-allergic or anti-inflammatory substituted (hetero)-aralkylamino-ortho-phenols
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Compounds of the general formula (I) or a pharmaceutically acceptable salt or solvate thereof;, wherein R1 is straight or branched C1-6alkyl, halo, nitro, cyano, hydroxy, or COR6 wherein R6 is straight or branch
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