The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer’s disease

Li, Hongmei; Qin, Jun; Dhondi, Pawan; Zhou, Wei; Vicarel, Monica; Bara, Thomas; Cole, David; Josien, Hubert; Pissarnitski, Dmitri; Zhu, Zhiwei; Palani, Anandan; Aslanian, Robert; Clader, John W.; Czarniecki, Michael; Greenlee, William J.; Cohen-Williams, Mary; Hyde, Lynn A.; Song, Lixin; Zhang, Lili; Chu, Inhou; Huang, Xianhai

doi:10.1016/j.bmcl.2012.11.055

Cited by 23 publications

(10 citation statements)

References 30 publications

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“…Structural modifications have been extensively performed on several classes of compounds. For example, analogs of the arylimidazole containing the olefin linker scaffold have been developed, namely oxadiazine (compounds 79 and 80 ) and oxadiazepine (compound 81 ) . Further studies substituted the olefin linker with a nitrogen linker as shown in aniline‐based compounds containing benzimidazole (compound 82 ), indazole (compound 83 ), benzoxazole (compound 84 ), pyrimidine fused with five‐ or six‐membered rings (compounds 85 ‐ 87 ) and pyrimidomorpholine (compounds 88 ‐ 90 ).…”

Section: γ‐Secretase Inhibitorsmentioning

confidence: 99%

“…For example, analogs of the arylimidazole containing the olefin linker scaffold have been developed, namely oxadiazine (compounds 79 and 80) and oxadiazepine (compound 81). 195,196 Further studies The importance of the arylimidazole moiety as a key scaffold for GSMs has also been emphasized as demonstrated by the thiazole-based compound identified from HTS (compound 94) (Figure 16). 199 The discovery of poor CNS drug-like issues still need to be addressed.…”

Section: γ-Secretase Inhibitorsmentioning

confidence: 99%

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Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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Section: γ‐Secretase Inhibitorsmentioning

confidence: 99%

Section: γ-Secretase Inhibitorsmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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“…Oxadiazepines have been shown to possess appreciable activity against gamma secretase modulator for the treatment of Alzheimer's disease . Furthermore, they have been found to exhibit diverse pharmacological effects, including antimicrobial, anticancer, herbicides and cytotoxicity activities .…”

Section: Optimization Of the Reaction Conditions[a]mentioning

confidence: 99%

Facile Intramolecular Cyclization of N‐(2‐Hydroxybenzoyl)hydrazones to N,N′‐Diacetyl Benzo‐1,3,4‐oxadiazepine Derivatives

2018

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“…The seven‐membered oxadiazepanes and triazepanes can be considered as homologues of morpholines and piperazines and are found in various bioactive small molecules directed against disease such as Alzheimer 's, diabetes, bacterial infections, and others . However, methods for their preparation lag behind those for saturated six‐membered N‐heterocycles.…”

Section: Introductionmentioning

confidence: 99%

Copper Promoted Oxidative Coupling of SnAP Hydrazines and Aldehydes to Form Chiral 1,4,5‐Oxadiazepanes and 1,2,5‐Triazepanes

Luescher

Songsichan

Hsieh

et al. 2017

Helvetica Chimica Acta

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SnAP (Sn (tin) amine protocol) hydrazine reagents and aldehydes undergo oxidative, copper mediated coupling to form substituted 1,4,5‐oxadiazepanes and 1,2,5‐triazepanes. Unlike all prior reactions involving SnAP reagents, the SnAP hydrazine reagents undergo a molecular oxygen‐assisted oxidative cyclization. The air‐ and moisture tolerant transformation accommodates a broad range of groups including electron‐rich, electron‐poor aromatic, heteroaromatic, and aliphatic aldehydes and is amenable to gram scale synthesis. These unusual, chiral heterocycles have unexpectedly large optical rotations, which may find use in optical materials.

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The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer’s disease

Cited by 23 publications

References 30 publications

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Facile Intramolecular Cyclization of N‐(2‐Hydroxybenzoyl)hydrazones to N,N′‐Diacetyl Benzo‐1,3,4‐oxadiazepine Derivatives

Copper Promoted Oxidative Coupling of SnAP Hydrazines and Aldehydes to Form Chiral 1,4,5‐Oxadiazepanes and 1,2,5‐Triazepanes

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