19932-85-5Relevant articles and documents
A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: Toward a new profile of indirect β-secretase inhibitors
Gay, Marion,Evrard, Caroline,Descamps, Florian,Carato, Pascal,Renault, Nicolas,Coevoet, Mathilde,Eddarkaoui, Sabiha,Baud, Catherine,Larchanché, Paul-Emmanuel,Buée, Luc,El Bakali, Jamal,Vingtdeux, Valérie,Sergeant, Nicolas,Melnyk, Patricia
, p. 104 - 125 (2018)
Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP by β-secretase (BACE-1) and γ-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Aβ peptide production. However, this effect is accompanied by an inhibition of lysosome-mediated degradation pathways. Following on from the promising activity of two series of APP metabolism modulators derived from CQ, we sought to develop new series of compounds that would retain the inhibitory effects on Aβ production without altering lysosome functions. Herein, we applied a ligand-based pharmacophore modeling approach coupled with de novo design that led to the discovery of a series of biaryl compounds. Structure-activity relationship studies revealed that minor modifications like replacing a piperidine moiety of compound 30 by a cyclohexyl (compound 31) allowed for the identification of compounds with the desired profile. Further studies have demonstrated that compounds 30 and 31 act through an indirect mechanism to inhibit β-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Aβ peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect β-secretase inhibitors.
Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy
Zhang, Xin,Chen, Huan,Lei, Yanqi,Zhang, Xiaonan,Xu, Long,Liu, Wenchao,Fan, Zhenya,Ma, Zequn,Yin, Zhechang,Li, Lingyun,Zhu, Changjin,Ma, Bing
, (2021/02/16)
Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
POLYAMINO BIARYL COMPOUNDS AND THEIR USE
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Page/Page column 38; 41-42, (2020/02/06)
The present invention is directed to novel compounds of Formula I and pharmaceutically acceptable salts or solvates thereof, and their use.
