554430-68-1Relevant academic research and scientific papers
POLYAMINO BIARYL COMPOUNDS AND THEIR USE
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Page/Page column 56-57, (2020/02/06)
The present invention is directed to novel compounds of Formula I and pharmaceutically acceptable salts or solvates thereof, and their use.
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 (2018/10/04)
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.
Synthesis of constrained raloxifene analogues by complementary use of Friedel-Crafts and directed remote metalation reactions
Kalinin, Alexey V.,Reed, Mark A.,Norman, Bryan H.,Snieckus, Victor
, p. 5992 - 5999 (2007/10/03)
New constrained heterocyclic analogues, 2a,b and 3, of Raloxifene (1) have been prepared by complementary Directed remote Metalation (DreM)/Friedel-Crafts cyclization approaches. Utilization of a benzylidene-thiolactone rearrangement was successfully impl
