Sulfonamido-aryl ethers as bradykinin B1 receptor antagonists

Cole, Andrew G.; Metzger, Axel; Brescia, Marc‐Raleigh; Qin, Lan-Ying; Appell, Kenneth C.; Brain, Christopher T.; Hallett, Allan; Ganju, Pam; Denholm, Alastair A.; Wareing, James R.; Ritchie, Timothy J.; Drake, Gillian M.; Bevan, Stuart; MacGloinn, Aisling; McBryde, Andrew; Patel, Viral; Oakley, Paul; Núñez, Ximena; Gstach, Hubert; Schneider, Peter; Baldwin, John J.; Dolle, Roland E.; McDonald, Edward; Henderson, Ian

doi:10.1016/j.bmcl.2008.11.005

Cited by 9 publications

(11 citation statements)

References 17 publications

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“…For the synthesis of the 9-HC hybrid 5i, featuring the N-(4hydroxy-3-methoxybenzyl)carboxamide moiety of capsaicin linked through a triazolylbutyl tether on position 9 of huprine, we first attempted a copper-catalyzed azide−alkyne cycloaddition (CuAAC) of an O-protected capsaicin-based 3butynamide to the previously reported racemic 9-azidobutylhuprine 13 60,64 capsaicin-based 3-butynamide, generated by coupling amine 6 with 3-butynoic acid, led to an inseparable 25:75 mixture of the desired 3-butynamide and its 2,3-butadienamide isomerization product. Fortunately, the amount of the isomerization byproduct was much lower (12%) when the O-TBDMS-protected amine 11 65 was used instead of 6. The byproduct and the desired 3-butynamide 12 could be separated by silica gel column chromatography, affording the latter in 36% yield.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Use of an O-TIPS-protected capsaicin-based 3-butynamide, generated by coupling amine 6 with 3-butynoic acid, led to an inseparable 25:75 mixture of the desired 3-butynamide and its 2,3-butadienamide isomerization product. Fortunately, the amount of the isomerization byproduct was much lower (12%) when the O-TBDMS-protected amine 11 was used instead of 6 . The byproduct and the desired 3-butynamide 12 could be separated by silica gel column chromatography, affording the latter in 36% yield.…”

Section: Resultsmentioning

confidence: 99%

“…To a solution of 3-methoxy-4-( tert -butyldimethylsilyloxy)benzylamine, 11 (2.10 g, 7.83 mmol) in CH 2 Cl 2 (40 mL), 3-butynoic acid (658 mg, 7.83 mmol), and EDC hydrochloride (1.18 g, 6.16 mmol) were successively added. The reaction mixture was stirred at rt for 2 h until complete consumption of the amine.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

et al. 2020

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The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

et al. 2020

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“…For the synthesis of the target triazole-based compounds 15 and 16 , the new alkyne 12 was first prepared by amide coupling of the know amine 11 [ 33 ] with 3-butynoic acid ( Scheme 2 ). Copper(I)-catalyzed Huisgen reaction of alkyne 12 with azides 7 and 8 afforded in good yields the O -TBDMS-protected triazole intermediates 13 and 14 , which were finally converted into the target triazole-containing tacrines 15 and 16 upon deprotection with camphorsulfonic acid (CSA) in MeOH or with tetrabutylammonium fluoride (TBAF) in THF, respectively ( Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis

et al. 2018

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Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.

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“…Although the aromatic compounds were generally superior, some of the tetrahydroquinolines displayed activity in the recombinant virus assay (RVA) . Several N -substituted tetrahydroquinoline derivatives (compounds 41 – 45 ) − have exhibited potent activities as allosteric inhibitors of the HIV-1 reverse transcriptase and also had good anti-HIV-1 activities. These compounds can thus be regarded as non-nucleoside reverse transcriptase inhibitors (NNRTIs), an increasingly important class of antiviral agents.…”

Section: Tetrahydroquinoline-based Bioactive Compoundsmentioning

confidence: 99%