Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs

Curtis, Michael; Vaillancourt, Valerie; Goodwin, Richard M.; Chubb, Nathan; Howson, William; McTier, Tom L.; Pullins, Aleah; Zinser, Erich W.; Meeus, Patrick; Woods, Debra J.; Hedges, Laura; Stuk, Tim; Price, Jeffrey E.; Koch, Jason; Menon, Sanjay

doi:10.1016/j.bmcl.2016.02.027

Cited by 18 publications

(8 citation statements)

References 12 publications

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“…A new class of antiparasiticide compounds has been recently discovered containing the compounds fluralaner (A1443; Fig. 1 ), afoxolaner and sarolaner [ 12 , 13 ]. Different studies have shown that isoxazolines act as specific blockers of GABACls and to a lesser extent of GluCls channels of insects [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)

Rufener¹,

Danelli²,

Bertrand

et al. 2017

Parasites Vectors

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BackgroundThe isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties.MethodsIn this study, we investigated the molecular mode of action and pharmacology of lotilaner. We report the successful gene identification, cDNA cloning and functional expression in Xenopus oocytes of Drosohpila melanogaster (wild type and dieldrin/fipronil-resistant forms), Lepeophtheirus salmonis (an ectoparasite copepod crustacean of salmon), Rhipicephalus microplus and Canis lupus familiaris GABACls. Automated Xenopus oocyte two-electrode voltage clamp electrophysiology was used to assess GABACls functionality and to compare ion channel inhibition by lotilaner with that of established insecticides addressing GABACls as targets.ResultsIn these assays, we demonstrated that lotilaner is a potent non-competitive antagonist of insects (fly) GABACls. No cross-resistance with dieldrin or fipronil resistance mutations was detected, suggesting that lotilaner might bind to a site at least partly different from the one bound by known GABACl blockers. Using co-application experiments, we observed that lotilaner antagonism differs significantly from the classical open channel blocker fipronil. We finally confirmed for the first time that isoxazoline compounds are not only powerful antagonists of GABACls of acari (ticks) but also of crustaceans (sea lice), while no activity on a dog GABAA receptor was observed up to a concentration of 10 μM.ConclusionsTogether, these results demonstrate that lotilaner is a non-competitive antagonist specific to invertebrate’s γ-aminobutyric acid-gated chloride channels (GABACls). They contribute to our understanding of the mode of action of this new ectoparasiticide compound.Electronic supplementary materialThe online version of this article (10.1186/s13071-017-2470-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)

Rufener¹,

Danelli²,

Bertrand

et al. 2017

Parasites Vectors

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“…Until recently, pet owners and practitioners had to rely on topical acaricidal treatments for the treatment and control of ticks on dogs. The recent development of oral formulations in the isoxazoline class of compounds, which had proved to be highly effective acaricides, provided an attractive alternative mode of treatment to topically administered products [10, 11]. Sarolaner, a new member of the isoxazoline class, has proved to be effective against the main tick species that infest dogs in countries both within the European Union (EU) and in the USA.…”

Section: Discussionmentioning

confidence: 99%

“…Sarolaner (Simparica™ chewable tablets) is a recently discovered, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs [10, 11]. Efficacy of this compound has previously been demonstrated against fleas [12–17], mites [18, 19], ticks [20–27] and ticks and fleas in combination [28, 29].…”

Section: Introductionmentioning

confidence: 99%

Immediate and persistent efficacy of sarolaner (Simparica™) against Haemaphysalis elliptica on dogs

et al. 2019

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Background The southern African yellow dog tick, Haemaphysalis elliptica , occurs in eastern and southern Africa and adults infest domestic and wild carnivores. This tick species is also a vector of the highly virulent Babesia rossi pathogen, the causative agent of canine babesiosis in sub-Saharan Africa. Sustained high levels of efficacy of a parasiticide are not only important in protecting dogs against the direct effects of tick infestation, but also in reducing the risk of tick-borne diseases. Sarolaner (Simparica™ chewable tablets) has been reported to be effective against the major tick species infesting dogs in Europe and the USA, including representatives from the genera Amblyomma , Ixodes , Rhipicephalus and Dermacentor. Until now no efficacy evaluations have been reported against species of the genus Haemaphysalis . The objective of the study was to confirm the efficacy of a single 2 mg sarolaner/kg oral dose of Simparica™ against induced infestations with H. ( R. ) elliptica , an important parasite of dogs in southern Africa. Methods This blinded, randomised, single centre, placebo controlled efficacy study followed a parallel group design and was conducted on two groups consisting of eight purpose-bred dogs each. Animals were treated orally, once on Day 0, with either a placebo compound (Group 1) or Simparica™ (Group 2). Simparica™ was administered orally at a dose rate of 2 mg sarolaner/kg body weight. The dogs were infested with ticks on Days − 7, − 2, 5, 12, 19, 26 and 33, with removal counts conducted on Days − 5, 2, 7, 14, 21, 28 and 35. Results A single oral administration of Simparica™ (sarolaner) at a minimum dose of 2 mg/kg resulted in a 100% efficacy against existing infestations of H. ( R. ) elliptica on dogs and a 100% reduction in live ticks following weekly re-infestations for 35 days. Moreover, the immediate and persistent high levels of efficacy observed in this study for 35 days is consistent with those observed in previous studies against ticks in other genera. Conclusions The efficacy of sarolaner (Simparica™), administered orally to dogs at the minimum label dose of 2.0 mg/kg, was demonstrated against existing and weekly re-infestations of H . ( R .) elliptica for at least 5 weeks. Efficacy of 100% was achieved against existing infestations as well as weekly re-infestations.

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“…Over the past 100 years treatment and control of this tick has focused on the development of an effective tick antiserum (developed in the 1930ʼs) and advancing veterinary critical care which has led to improved survival of pets ( Padula et al, 2020 ). The biggest advance in the prevention and control of ticks and their associated diseases has been made in the development of highly effective ectoparasiticides such as the isoxazolines ( Ozoe et al., 2010 ; Gassel et al., 2014 ; Shoop et al., 2014 ; Curtis et al, 2016 ; McTier et al., 2016 ; Rufener et al, 2017 ). These potent broad-spectrum ectoparasiticides have long-lasting systemic action against ticks (e.g.…”

Section: Introductionmentioning

confidence: 99%

Protecting dogs and cats against the Australian paralysis tick, Ixodes holocyclus (Acari: Ixodidae): A review of the Australian acaricide registration process

Roeber¹,

Webster²

2021

Current Research in Parasitology & Vector-Borne Diseases

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Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs

Cited by 18 publications

References 12 publications

The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)

The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)

Immediate and persistent efficacy of sarolaner (Simparica™) against Haemaphysalis elliptica on dogs

Protecting dogs and cats against the Australian paralysis tick, Ixodes holocyclus (Acari: Ixodidae): A review of the Australian acaricide registration process

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