Molecular hybridization yields triazole bronchodilators for the treatment of COPD

Jones, Lyn H.; Burrows, Jane L.; Feeder, Neil; Glossop, Paul A.; James, K.; Jones, Rhys; Kenyon, Amy S.; Patel, Sheena; Roberts, Dannielle F.; Selby, Matthew D.; Strang, Ross S.; Stuart, Emilio F.; Trevethick, Michael A.; Watson, Jessica; Wright, Kate; Clarke, Nick

doi:10.1016/j.bmcl.2015.10.008

Cited by 8 publications

(2 citation statements)

References 18 publications

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“…The prodrug design consisted of the parent drug bound to a lung-retentive moiety via a linker group, which bioactivates at a controlled rate to liberate the active drug molecule alongside nontoxic side products. To test the feasibility of this approach, we chose to functionalize the known muscarinic M 3 receptor antagonist 1 , an active metabolite of enpiperate, − as 1 possesses the required synthetic handle that can be readily modified with our recently disclosed pH-sensitive linking group (Figure ). …”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

et al. 2022

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A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate ( 1 ) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-((( R )-2-(( S )-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate ( 23 ), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

et al. 2022

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“…Brexipiprazole is a successor of the top-selling generic antipsychotic agent, Aripiprazole. Targets on this scaffold, β-adrenergic receptors [2][3][4][5], muscarinic acetylcholine receptors [6][7][8], vascular endothelial growth factor receptors [9,10], poly [ADP-ribose] polymerase-1 [11][12][13][14][15], tyrosine-protein kinases [16], and serine/threonine-protein kinases [17][18][19], have been extensively studied for decades. In addition In addition, 2-quinolones are embedded as core structures in natural products [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in One-Pot Modular Synthesis of 2-Quinolones

2020

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It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.

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Quinolone–Triazole Hybrids and their Biological Activities

Fan

Zhou

2018

Journal of Heterocyclic Chem

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Hybridization, a strategy based on the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, represents an encourage approach in the development of new drugs with potential therapeutic application in several pathologies. Triazoles and quinolones occupy an important position in medicinal chemistry attribute to their various biological activities, so hybridization of these two pharmacophores may provide more effective candidates that might be able to prevent the drug resistance. This review outlines the biological activities of triazole–quinolone hybrids, and discusses their structure–activity relationship.

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Molecular hybridization yields triazole bronchodilators for the treatment of COPD

Cited by 8 publications

References 18 publications

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

Recent Advances in One-Pot Modular Synthesis of 2-Quinolones

Quinolone–Triazole Hybrids and their Biological Activities

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