Triazoles as γ-secretase modulators

Fischer, Christian; Zultanski, Susan L.; Zhou, Hua; Methot, Joey L.; Brown, William C.; Mampreian, Dawn M.; Schell, Adam; Shah, Sanjiv; Nuthall, Hugh; Hughes, Bethany; Smotrov, Nadja; Kenific, Candia M.; Cruz, Jonathan C.; Walker, Deborah; Bouthillette, Melanie; Nikov, George N.; Savage, Dan F.; Jeliazkova-Mecheva, Valentina V.; Diaz, Damaris; Szewczak, Alexander A.; Bays, Nathan; Middleton, Richard E.; Muñoz, Benito; Shearman, Mark S.

doi:10.1016/j.bmcl.2011.04.089

Cited by 14 publications

(13 citation statements)

References 22 publications

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“…22d Our work began by replacing the styrenyl moiety of E2012 with heterocycles, leading to a series of potent 1,2,3-triazoles such as 1 where the azole hydrogen bond acceptor was important for activity. 23 Compound 1 and many related triazoles had hERG binding activity, which was generally mitigated through the incorporation of amides or lactams, such as lactam 2. 24 Over the course of addressing hERG, polar surface area also increased to >75 Å.…”

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confidence: 99%

Potent benzoazepinone γ-secretase modulators with improved bioavailability

Methot

Fischer

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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confidence: 99%

Potent benzoazepinone γ-secretase modulators with improved bioavailability

Methot

Fischer

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…[22] Final compounds 17 , 18 , and 19 were prepared via click chemistry, starting from prop-2-yn-1-yl N -cyclohexylcarbamate, [23] prepared by reaction of cyclohexylamine with the commercially available prop-2-ynyl chloroformate, and the azides 5a , 5b , and 5c , respectively (Scheme 2). Then, copper catalyzed [3 + 2] cycloaddition reaction between azides 5a and 5b with the commercially available but-3-yn-1-ol, allowed us to obtain compounds 31a and 31b in acceptable yields.…”

Section: Resultsmentioning

confidence: 99%

“…Aromatic azide 5 a was prepared from aniline by a diazotation-azidation protocol, [21] while 5 b, 5 c, and 6-16 were obtained in good to excellent yields by reacting the corresponding halides with sodium azide. [22] Final compounds 17, 18, and 19 were prepared via click chemistry, starting from prop-2-yn-1-yl N-cyclohexylcarbamate, [23] prepared by reaction of cyclohexylamine with the commercially available prop-2-ynyl chloroformate, and azides 5 a, 5 b, and 5 c, respectively (Scheme 2). Then, copper catalyzed [3+2] cycloaddition reaction between azides 5 a and 5 b with the commercially available but-3-yn-1ol, allowed us to obtain compounds 31 a and 31 b in acceptable yields.…”

Section: Resultsmentioning

confidence: 99%

O‐(Triazolyl)methyl Carbamates as a Novel and Potent Class of Fatty Acid Amide Hydrolase (FAAH) Inhibitors

et al. 2014

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Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed. O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, we synthesized a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives exploiting the copper-catalyzed [3 + 2] cycloaddition reaction between azides and alkynes (click chemistry). We explored structure-activity relationships within this new class of compounds and identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range.

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“…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 ) . The discovery of this compound has led to the design of the later nonaniline GSMs including arylimidazole‐containing derivatives of thiazole (compounds 95 and 96) , triazole (compounds 97 ‐ 101 ), amide (compound 102 ), and pyridopyrazine 1,6‐dione (compounds 103 and 104 ) (Figure ) . Most of these compounds exhibited good potency, but poor drug‐like properties.…”

Section: γ‐Secretase Inhibitorsmentioning

confidence: 99%

“…this compound has led to the design of the later nonaniline GSMs including arylimidazole-containing derivatives of thiazole (compounds 95 and 96), triazole (compounds 97-101), amide (compound 102), and pyridopyrazine 1,6dione (compounds 103 and 104) (Figure 16) [200][201][202][203][204][205][206]. Most of these compounds exhibited good potency, but poor drug-like properties.…”

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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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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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Triazoles as γ-secretase modulators

Cited by 14 publications

References 22 publications

Potent benzoazepinone γ-secretase modulators with improved bioavailability

Potent benzoazepinone γ-secretase modulators with improved bioavailability

O‐(Triazolyl)methyl Carbamates as a Novel and Potent Class of Fatty Acid Amide Hydrolase (FAAH) Inhibitors

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

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