Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors

Close, Joshua; Heidebrecht, Richard W.; Hendrix, John E.; Li, Chaomin; Munoz, Ben; Surdi, Laura; Kattar, Solomon D.; Tempest, Paul; Moses, P.; Geng, Xiaoliu; Hughes, Bethany; Smotrov, Nadya; Moxham, Chris; Chapnick, Jennifer; Kariv, Ilona; Nikov, George N.; Burke, Julie Elizabeth; Deshmukh, Sujal V.; Jeliazkova-Mecheva, Valentina V.; Leach, J. K.; Diaz, Damaris; Xu, Lin; Yang, Ziping; Kwei, Gloria Y.; Moy, Lily Y.; Shah, Sanjiv; Tanga, Flobert; Kenefic, Candia; Savage, Dan F.; Shearman, Mark S.; Ball, Richard G.; McNevin, Michael J.; Markarewicz, Amanda; Miller, Thomas A.

doi:10.1016/j.bmcl.2012.03.038

Cited by 5 publications

(1 citation statement)

References 30 publications

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“…It has been found that piperdine ( Figure 4) hybrids act as γ-secretase modulators, with high in vitro and in vivo anti-Aβ 42 potency [29][30][31][32], Aβ 42 aggregation inhibitors, AChE-induced Aβ aggregation [33], moderate to good AChE inhibitory activity [33,34] and positive metal-chelating ability [35]. Morpholine (Figure 4) contributes to decreased metal-induced (Fe and Cu) Aβ aggregation [36]; reduces Aβ toxicity, e.g.…”

Section: Conjugated Moieties (Piperidine Morpholine Thiophene and Ementioning

confidence: 99%

Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Repsold

Malan

Joubert

et al. 2018

SAR and QSAR in Environmental Research

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Alzheimer's Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin-morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin-piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys Discovery Studio V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.

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