Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

Hybrid inhibitors of acetyl-and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin-donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase. K E Y W O R D S biological activity, drug design, hydrolases, medicinal chemistry, structure-activity relationship Arch Pharm Chem Life Sci. 2018;351:e1800194.wileyonlinelibrary.com/journal/ardp

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“…18b : The product was obtained as yellow oil in 61% yield (1.61 g). Analytical data are in agreement with the literature reports …”

Section: Methodssupporting

confidence: 91%

Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments

Łozińska

Świerczyńska

Molęda

et al. 2018

Archiv der Pharmazie

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“…Vessel stenosis or stasis promotes thrombosis. Other triggers are often used to induce formation of large thrombi [49]–[53].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Antithrombotic Activity of Thrombin DNA Aptamers by a Murine Thrombosis Model

et al. 2014

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Aptamers are nucleic acid based molecular recognition elements with a high potential for the theranostics. Some of the aptamers are under development for therapeutic applications as promising antithrombotic agents; and G-quadruplex DNA aptamers, which directly inhibit the thrombin activity, are among them. RA-36, the 31-meric DNA aptamer, consists of two thrombin binding pharmacophores joined with the thymine linker. It has been shown earlier that RA-36 directly inhibits thrombin in the reaction of fibrinogen hydrolysis, and also it inhibits plasma and blood coagulation. Studies of both inhibitory and anticoagulation effects had indicated rather high species specificity of the aptamer. Further R&D of RA-36 requires exploring its efficiency in vivo. Therefore the development of a robust and adequate animal model for effective physiological studies of aptamers is in high current demand. This work is devoted to in vivo study of the antithrombotic effect of RA-36 aptamer. A murine model of thrombosis has been applied to reveal a lag and even prevention of thrombus formation when RA-36 was intravenous bolus injected in high doses of 1.4–7.1 µmol/kg (14–70 mg/kg). A comparative study of RA-36 aptamer and bivalirudin reveals that both direct thrombin inhibitors have similar antithrombotic effects for the murine model of thrombosis; though in vitro bivalirudin has anticoagulation activity several times higher compared to RA-36. The results indicate that both RA-36 aptamer and bivalirudin are direct thrombin inhibitors of different potency, but possible interactions of the thrombin-inhibitor complex with other components of blood coagulation cascade level the physiological effects for both inhibitors.

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“…Acting as pharmacodynamics targets . Some tetrahydroquinolines acting on ion channels compounds 25 – 27 [180–183] (Figure 5), membrane receptors compounds 28 – 35 [184–194] (Figure 6), steroid hormone receptors compounds 36 – 46 [21,195–205] (Figure 7), and nonsteroid hormone receptors compounds 47–54 [206–224] (Figure 8).…”

Section: The Strategies For Hydrogenationmentioning

confidence: 99%

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

El‐Shahat

2021

Journal of Heterocyclic Chem

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The pursuit of modern sustainable chemistry has stimulated the development of innovative catalytic processes that enable chemical transformations to be performed under mild and clean conditions with high efficiency. Herein, we report that the hydrogenation of heteroaromatic compounds is one of the most efficient methods for the construction of heterocyclic skeletons, and only a few promising progress has been achieved. Transition metal‐catalyzed, a countless number of transition metals include have been used toward the development of homo/heterogeneous hydrogenation of quinolines via the most convenient route (Direct Hydrogenation) to obtain the corresponding tetrahydroquinoline derivatives.

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Design and Synthesis of Thrombin Inhibitors: Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

Cited by 29 publications

References 45 publications

Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments

Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments

Evaluation of Antithrombotic Activity of Thrombin DNA Aptamers by a Murine Thrombosis Model

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

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