Sarolaner (450 nM-1 mM; 5 minutes) suppresses currents produced by gamma-buffered butyric acid (GABA) on CfRDL-A285 and CfRDL-S285 receptors [1].

Sarolaner (450 nM-1 mM; 5 minutes) suppresses currents produced by gamma-buffered butyric acid (GABA) on CfRDL-A285 and CfRDL-S285 receptors [1].

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Sarolaner demonstrated potent activity against cat fleas (C. felis felis) in a blood feeding assay with an LC80 of 0.3 µg/mL. [1]
Sarolaner demonstrated potent activity against soft ticks (Ornithodoros turicata) in a blood feeding assay with an LC100 of 0.003 µg/mL. [1]
In a head-to-head comparative in vitro assay with afoxolaner and fluralaner, sarolaner demonstrated superior potency against fleas (LC80 = 0.1 µg/mL) and soft ticks (LC100 = 0.03 µg/mL). [1]
Sarolaner potently blocked GABA-induced currents in recombinant CHO-K1 cells stably expressing cat flea RDL GABACl subunits. It showed no agonist activity. The IC50 for inhibition was 135 ± 33 nM for the susceptible CRDL-A285 channel and 136 ± 16 nM for the resistant CRDL-S285 channel. [1]
In a side-by-side comparison using the same assay, sarolaner was significantly more potent (IC50 ~135-136 nM) than afoxolaner (IC50 ~412-539 nM) at inhibiting GABA-induced currents in both susceptible and resistant flea GABACls. [1]
Sarolaner exhibited similar potency against both dieldrin-susceptible and dieldrin-resistant (A285S mutation) flea GABACl alleles, unlike dieldrin which showed significantly reduced potency against the resistant allele. [1]

Sarolaner shown 100% effectiveness against R at 2.5 mg/kg; main sidewall. sanguineus as well as D. reticuLatus [1]. Sarolaner, which acts against I, is efficacious at 1.25–5 mg/kg (primary sidewall). ricinus [1].

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In dogs, a single oral dose of sarolaner at 2.5 mg/kg (solution) provided 100% efficacy against existing infestations of cat fleas (C. felis) and brown dog ticks (Rhipicephalus sanguineus) at 48 hours post-treatment. [1]
The same dose (2.5 mg/kg) provided ≥99.9% efficacy against weekly re-infestations of cat fleas for 35 days. [1]
Against R. sanguineus, the 2.5 mg/kg dose provided 100% efficacy for 35 days against weekly re-infestations. [1]
Against Dermacentor reticulatus ticks, the 2.5 mg/kg dose provided ≥98.0% efficacy for 35 days against weekly re-infestations. [1]
In a dose-finding study against Ixodes ricinus ticks, sarolaner administered as an oral suspension at 1.25, 2.5, and 5 mg/kg provided 100% efficacy against an existing infestation at 48 hours post-treatment. [1]
Against subsequent re-infestations, the 1.25 mg/kg dose provided ≥99.3% efficacy for 35 days (efficacy was 80.1% on Day 57). The 2.5 and 5 mg/kg doses provided >99.3% efficacy through Day 57. [1]

Cell Viability Assay[1]
Cell Types: CHO-K1 Cell
Tested Concentrations: 450 nM-1 mM
Incubation Duration: 5 minutes
Experimental Results: Inhibition of GABA-elicited current of susceptible fleas (CfRDL-A285) and resistant fleas GABACl, EC50 is 135 respectively and 136 nM.

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Voltage-clamp electrophysiology studies were conducted using CHO-K1 cells stably expressing recombinant cat flea (C. felis) RDL GABA-gated chloride channel subunits (CRDL-A285 and CRDL-S285). [1]
A cell suspension was prepared immediately prior to studies. Experiments were performed on an automated patch-clamp platform. The external solution was a HEPES-buffered saline. The internal solution contained a potassium-based salt and a perforating agent. All recordings were made at room temperature with cells held at -80 mV. [1]
For agonist testing, GABA was diluted in external solution. An eight-point, 3-fold serial dilution series was prepared from a stock solution. Test compounds were added via an integrated pipettor. Recordings were sampled before and after compound addition. Peak inward current was determined. Concentration-response data were fit using non-linear regression to determine EC50. [1]
For antagonist testing, an eight-point concentration series of the test compound was constructed. After test compound addition and recording, an approximate EC80 concentration of GABA was added to evaluate the inhibitory activity of the test compound. Recordings were sampled before and after agonist addition. Percent inhibition of GABA-induced current was calculated. Concentration-response curves were constructed and fit to determine IC50. [1]

Animal/Disease Models: Dogs infected with R. sanguineus and D. reticulatus [1]
Doses: 2.5 mg/kg
Route of Administration: po (oral gavage); 2.5 mg/kg One time
Experimental Results:100% efficacy against R. sanguineus 48 hrs (hrs (hours)) after treatment , also has 98.0% efficacy against D. d. Net pattern.

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Animal/Disease Models: Ricin-infected dogs [1] Doses: 1.25, 2.5 and 5 mg/kg
Route of Administration: po (oral gavage); 1.25, 2.5 and 5 mg/kg Primary
Experimental Results: Prior to 7 days, all doses were effective in ricin Both narcotics demonstrated 100% efficacy and diminished subsequent reinfections by more than 99.3% by 57 days at doses of 5.0 and 2.5 mg/kg.

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An exploratory margin of safety study in adult Beagle dogs: Sarolaner was formulated in capsules with excipients (microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, magnesium stearate) and administered orally at doses of 2, 6, or 10 mg/kg. Each treatment group was dosed three times at 28-day intervals. A full post-mortem examination was conducted one week after the third dose. [1]
An exploratory tolerance study in 8-week-old Beagle dogs: Sarolaner was formulated similarly in capsules and administered orally at doses of 4, 12, or 20 mg/kg. Each dog was dosed twice at a 28-day interval, followed by a complete post-mortem examination one week after the second dose. [1]
A parallel-design bioavailability study in Beagle dogs: Sarolaner was administered either as an intravenous solution at 2 mg/kg or as a compressed tablet for oral administration (20 mg/dog, dose range 2.17–3.79 mg/kg). Dogs were fasted overnight prior to dosing. Blood samples for pharmacokinetic analysis were collected through Day 56. [1]
Efficacy Study 1 in dogs: Dogs were treated via oral gavage with either a placebo control or a sarolaner solution (5 mg/mL in a tetraglycol/solutol base) to provide a dose of 2.5 mg/kg. [1]
Efficacy Study 2 in dogs: Dogs were treated via oral gavage with either a placebo control, or a sarolaner suspension formulated in a carboxymethylcellulose/Tween-80 base with water at concentrations to provide doses of 1.25, 2.5, or 5 mg/kg. [1]

Following intravenous administration of a 2 mg/kg dose to dogs, the steady-state volume of distribution (Vdss) was 2.81 L/kg, and the clearance (CL) was 0.12 mL/min/kg. [1] Saloranar is rapidly and well absorbed after oral administration. The time to peak concentration (Tmax) is reached on the first day after administration. [1] The bioavailability of saloranar after oral administration to dogs on an empty stomach is calculated to be >85%. [1] The elimination half-life (T1/2) of saloranar is calculated to be 11–12 days. [1] Plasma concentrations of saloranar are dose-dependent in the range of 1.25 to 5 mg/kg oral doses in dogs. [1] Saloranar has a high protein binding rate (>99.9%). [1]
After oral administration of 20 mg/dog (dose standardized to 2 mg/kg), the least squares mean maximum plasma concentration (Cmax) was 1100 ng/mL. [1]

In a mouse symptom screening model, oral doses of sarolana up to 30 mg/kg did not cause any adverse reactions. [1] In an exploratory safety study in dogs, adult dogs were given oral sarolana at doses of 2, 6, and 10 mg/kg three times every 28 days; 8-week-old puppies were given oral sarolana at doses of 4, 12, and 20 mg/kg twice every 28 days. All dose levels were well tolerated and no adverse reactions were observed. [1] Toxicokinetic assessments showed that systemic exposure in both adult and puppies was dose-dependent. Clinical pathology, gross pathology, organ weight, and histopathology related to the test substance were minimal and not considered adverse or clinically significant. [1]

[1]. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs. Vet Parasitol. 2016 May 30;222:3-11.

See also: Moxidectin; Praziquantel; Saloranal (ingredient); Saloranal; Selamectin (ingredient).

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Drug Indications
For the treatment of tick infestations (Reticulate Tick, Hexagonal Ixodile, Ricinus communis, and Red-brown Ixodile). This veterinary drug has immediate and sustained tick-killing activity, with efficacy lasting at least 5 weeks. For the treatment of flea infestations (Ctenophora catinatum and Ctenophora caninatum). This veterinary drug has immediate and sustained killing activity against newly infected fleas, with efficacy lasting at least 5 weeks. This veterinary drug may be used as part of a treatment regimen for flea allergic dermatitis (FAD). For the treatment of scabies. For the treatment of ear mite infestations (canine ear mites). For the treatment of canine demodicosis. Fleas and ticks must attach to a host and begin feeding on blood to access the active ingredient. For the treatment of tick infestations (Reticulate Tick, Hexagonal Ixodile, Ricinus communis, and Red-brown Ixodile). This veterinary drug has immediate and sustained tick-killing activity, with efficacy lasting at least 5 weeks. It is used to treat flea infestations (cat fleas and dog fleas). This veterinary drug has immediate and sustained tick-killing activity against newly infected fleas, with efficacy lasting at least 5 weeks. This veterinary drug can be used as part of a treatment regimen for flea allergic dermatitis (FAD). It is used to treat scabies (Sarcoptes scabiei), ear mites (Otodectes cynotis), and canine demodicosis (Demodex canis). Fleas and ticks must attach to a host and begin feeding on blood to come into contact with the active substance.

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Salorana is a novel isoxazoline ectoparasite killer, specifically discovered and developed for use in companion animals (dogs). [1]
The molecule is a chiral pure S-enantiomer. The flea and tick activity is entirely contained in this enantiomer; the R-enantiomer is inactive. [1]
Its chemical structure consists of four subunits: a substituted phenyl head, an isoxazoline core, a spirocyclic aza-butane benzofuran moiety, and a methanesulfonyl ethyl ketone tail. [1]
This compound was discovered in a lead compound optimization project that prepared and tested over 3,000 isoxazoline compounds. [1]
Its main mechanism of action is the inhibition of invertebrate ligand-gated chloride channels (GABA-gated chloride channels). [1]
This compound is intended for use as a once-monthly oral medication to control fleas and ticks on dogs. [1]

C23H18CL2F4N2O5S

581.364037036896

580.025

1398609-39-6

73169092

White to off-white solid powder

4.781

0

10

4

37

1050

1

CS(=O)(=O)CC(=O)N1CC2(C1)C3=C(CO2)C=C(C=C3)C4=NO[C@@](C4)(C5=CC(=C(C(=C5)Cl)F)Cl)C(F)(F)F

FLEFKKUZMDEUIP-QFIPXVFZSA-N

InChI=1S/C23H18Cl2F4N2O5S/c1-37(33,34)9-19(32)31-10-21(11-31)15-3-2-12(4-13(15)8-35-21)18-7-22(36-30-18,23(27,28)29)14-5-16(24)20(26)17(25)6-14/h2-6H,7-11H2,1H3/t22-/m0/s1

(S)-1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one

PF6450567; PF 6450567; PF-6450567

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~300 mg/mL (~516.03 mM)

Solubility in Formulation 1: ≥ 7.5 mg/mL (12.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 75.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 7.5 mg/mL (12.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 75.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)