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  • Two intermediate compounds A and


    Two intermediate compounds (A and B in Fig. 1) were tested for both Aβ40 and CYP3A4 inhibition activity. Potential hydrolysis of structures I and IIin vivo may produce A which is a strong CYP3A4 inhibitor. Cyclopropanol group is a suspected liability, because desipramine sale B without it has a clean CYP3A4 profile. However, cyclopropyl is important for γ-secretase activity. Based on these known results, herein we describe the design, synthesis, SAR, and biological profile of a novel substituted morpholine sulfonamide series of GSIs III[11]. Borrowing SAR elements of known sulfonamide GSIs, one carbon on the piperidine ring was replaced by oxygen; carbamate right hand side was changed to amide to avoid the potential generation of cyclopropanol group from in vivo hydrolysis. An optional hydroxyl group was also added at R5 position of III to expand SAR by analogy to structure II. Selected compounds of type III demonstrated a significant reduction of amyloid-β (Aβ) after acute oral dosing in a transgenic animal model of AD.
    Results and discussion
    Conclusion In conclusion, based on the SAR elements of known sulfonamide GSIs from our previous research results, we have designed a novel series of morpholine sulfonamide core series of GSIs. The new substituted morpholine series did not only improved the in vitro activity significantly, but also reduced the CYP3A4 liability. Selected compound 15a demonstrated significant reduction of total Aβ after acute oral dosing in a transgenic animal model of AD.
    Dementia affects nearly 36 million people worldwide, a number which is expected to triple by 2050. The most common form of dementia is Alzheimer’s disease (AD), a progressive, neurodegenerative illness described in 1906 by the German physician Alois Alzheimer. No treatment exists yet for this condition, the marketed drugs targeting only the amelioration of the symptoms. Characteristic for AD is the deposition of extraneuronal amyloid plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein in the limbic and cortical regions of the brain, which eventually leads to neurodegeneration. Based on genetic evidence, Hardy and Higgins formulated the amyloid hypothesis, according to which accumulation of amyloid peptides in the brain is the primary driver of the AD, Formation of the amyloid beta peptides in the brain is the result of a sequence of proteolytic cleavages of amyloid precursor protein, APP. This is first cleaved by β-secretase (BACE-1) to form a membrane bound C-terminal fragment (C99), which is further cleaved by gamma secretase (GS) to produce Aβ peptides of lengths varying from 37 to 43 aminoacids. Of these, Aβ42 and Aβ43 are most prone to aggregate and generate the neurotoxic amyloid plaques. The amyloid cascade theory opened the door to anti Aβ therapeutics as strategies for developing anti Alzheimer disease modifying drugs, among which suppression of the Aβ42 production via BACE-1 inhibition and GS inhibition or modulation is intensively pursued. In this regard, GS, the intra-membrane protease complex responsible for the final cleavage step in the amyloid cascade, represents an attractive yet challenging target. Recently, GS inhibitors (GSIs) semagacestat and avagacestat were discontinued in clinical trials due to side effects such as toxicity related to inhibition of other GS substrates and decline in cognition., GS modulators (GSMs),, a class of compounds which are able to reduce the level of longer, neurotoxic Aβ peptides by shifting the APP processing of γ-secretase towards shorter isoforms (such as Aβ37, Aβ38), represent a viable alternative to GS inhibition. Several classes of GSMs are known to date: carboxylic acids derived from non-steroidal anti-inflammatory drugs (NSAIDs), such as tarenflurbil, non-NSAID GSMs such as aryl imidazole-derived GSMs and more recently, triterpene-derived modulators.