- Design, synthesis, and biological evaluation of furosemide analogs as therapeutics for the proteopathy and immunopathy of Alzheimer's disease
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β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer's disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.
- Liu, Xiaojing,Pasangulapati, Jagadeesh Prasad,Schier, Stephanie (Wohnig),Stover, Kurt R.,Wang, Yanfei,Wang, Zhiyu,Weaver, Donald F.
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supporting information
(2021/07/28)
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- FUROSEMIDE ANALOGUES AND COMPOSITIONS AND USES THEREOF FOR TREATMENT OF ALZHEIMER'S DISEASE
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The present application provides furosemide analogues of the general formula Z having activity as anti-Aβ aggregation agents and/or as inhibitors of Aβ induced neuroinflammation. Formula Z These compounds are useful in preventing, delaying and/or treating Alzheimer's Disease. Accordingly, the present application further provides pharmaceutical compositions and method for preventing, delaying and/or treating Alzheimer's Disease.
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Paragraph 0056; 0059-0061; 0066-0067
(2021/01/23)
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- Synthetic method of Azosemide intermediate
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The invention discloses a synthesis method of an azeosemide intermediate, wherein the synthesis method comprises the following steps: (1) catalytic sulfonation reaction: carrying out catalytic sulfonation reaction on 4-chloro-2-fluorobenzoic acid and chlo
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Paragraph 0026-0035
(2020/10/04)
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- Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile
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We recently described (J. Med. Chem. 2008, 51, 6538-6546) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further finetuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
- Kazmierski, Wieslaw M.,Anderson, Don L.,Aquino, Christopher,Chauder, Brian A.,Duan, Maosheng,Ferris, Robert,Kenakin, Terrence,Koble, Cecilia S.,Lang, Dan G.,Mcintyre, Maggie S,Peckham, Jennifer,Watson, Christian,Wheelan, Pat,Spaltenstein, Andrew,Wire, Mary B.,Svolto, Angilique,Youngman, Michael
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scheme or table
p. 3756 - 3767
(2011/07/30)
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds, compositions and combinations thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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Page/Page column 44-45
(2008/12/06)
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