Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds

Ducray, Pierre; Gauvry, Noe͏̈lle; Pautrat, François; Goebel, Thomas; Fruechtel, Joerg; Desaules, Yves; Weber, Sandra; Bouvier, Jacques; Wagner, Trixie; Froelich, Olivier; Kaminsky, Ronald

doi:10.1016/j.bmcl.2008.03.071

Cited by 57 publications

(52 citation statements)

References 12 publications

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“…Monepantel (AAD-1566) and AAD-2224 are optical enantiomers, S and R, respectively (Ducray et al, 2008), the former being almost 1000-fold more active against H. contortus than the latter. It is noteworthy that the two enantiomers affect H. contortus DEG-3/DES-2 channel function in opposite directions: whereas monepantel potentiates late currents, AAD-2224 inhibits them (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Monepantel (Zolvix; Novartis Animal Health, Basel, Switzerland) is the first new anthelmintic to be introduced for livestock for more than 27 years (Kaminsky et al, 2008a,b). Monepantel belongs to a new class of anthelmintics, the amino-acetonitrile derivatives (AADs) (Ducray et al, 2008). Monepantel is able to control infections of nematode isolates resistant to all of the classic anthelmintics (Kaminsky et al, 2008b), indicating that the AADs have a different mode of action.…”

Section: Introductionmentioning

confidence: 99%

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Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal NematodeHaemonchus contortus

Rufener¹,

Baur²,

Kaminsky³

et al. 2010

Mol Pharmacol

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Monepantel is the first drug of a new family of anthelmintics, the amino acetonitrile derivatives (AAD), presently used to treat ruminants infected with gastrointestinal nematodes such as Haemonchus contortus. Monepantel shows an excellent tolerability in mammals and is active against multidrug-resistant parasites, indicating that its molecular target is absent or inaccessible in the host and is different from those of the classic anthelmintics. Genetic approaches with mutant nematodes have suggested acetylcholine receptors of the DEG-3 subfamily as the targets of AADs, an enigmatic clade of ligand-gated ion channels that is specific to nematodes and does not occur in mammals. Here we demonstrate direct interaction of monepantel, its major active metabolite monepantel sulfone, and other AADs with potential targets of the DEG-3 subfamily of acetylcholine receptors. H. contortus DEG-3/DES-2 receptors were functionally expressed in Xenopus laevis oocytes and were found to be preferentially activated by choline, to permeate monovalent cations, and to a smaller extent, calcium ions. Although monepantel and monepantel sulfone did not activate the channels by themselves, they substantially enhanced the late currents after activation of the channels with choline, indicating that these AADs are type II positive allosteric modulators of H. contortus DEG-3/DES-2 channels. It is noteworthy that the R-enantiomer of monepantel, which is inactive as an anthelmintic, inhibited the late currents after stimulation of H. contortus DEG-3/DES-2 receptors with choline. In summary, we present the first direct evidence for interaction of AADs with DEG-3-type acetylcholine receptors and discuss these findings in the context of anthelmintic action of AADs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal NematodeHaemonchus contortus

Rufener¹,

Baur²,

Kaminsky³

et al. 2010

Mol Pharmacol

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“…Recently, a new class of anthelmintic, the amino-acetonitrile derivatives (AADs), has been discovered by Novartis Animal Health Inc. [2,3]. AADs are a class of low molecular mass compounds bearing different aryloxy and aroyl moieties on an amino-acetonitrile core.…”

Section: Introductionmentioning

confidence: 99%

Determination of the new anthelmintic monepantel and its sulfone metabolite in milk and muscle using a UHPLC–MS/MS and QuEChERS method

Kinsella

Byrne

Cantwell

et al. 2011

Journal of Chromatography B

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“…The AADs are a new class of synthetic anthelmintics with broad spectrum activity against nematodes that are resistant to the benzimidazoles, imidazothiazoles and macrocyclic lactones [54–56]. Monepantel, also known as AAD 1556, is the first member of this class to be developed for the control of a broad range of parasitic nemtaodes in sheep (Figure 5) [56].…”

Section: Introductionmentioning

confidence: 99%

A brief review on the mode of action of antinematodal drugs

2017

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Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs. As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds. It is also necessary to identify new drug targets and drugs for the continued effective control of nematode parasites.

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Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds

Cited by 57 publications

References 12 publications

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal NematodeHaemonchus contortus

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal NematodeHaemonchus contortus

Determination of the new anthelmintic monepantel and its sulfone metabolite in milk and muscle using a UHPLC–MS/MS and QuEChERS method

A brief review on the mode of action of antinematodal drugs

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