GABA receptors

The IC50 values of lotilaner for the GABACl receptors of Drosophila dieldrin/flupron formaldehyde-resistant form (DmR2), Lepeophtheirus Salmonis (Ls), and Rhipicephalus microplus (Rm) are 38.25 ± 3.75, 52.40 ± 4.54, and 36.79 ± 4.39 nM, respectively [1 ‑.

For the treatment of flea and tick infestations. Fleas and ticks must attach to the host and commence feeding in order to be exposed to the active substance. The veterinary medicinal product can be used as part of a treatment strategy for the control of flea allergy dermatitis (FAD). DogsThis veterinary medicinal product provides immediate and persistent killing activity for 1 month for fleas (Ctenocephalides felis and C. canis) and ticks (Rhipicephalus sanguineus, Ixodes ricinus, I. hexagonus and Dermacentor reticulatus). CatsThis veterinary medicinal product provides immediate and persistent killing activity for 1 month against fleas (Ctenocephalides felis and C. canis) and ticks (Ixodes ricinus).
Lotilaner is an ectoparasiticide that is a member of the isoxazoline family of compounds. Lotilaner has largely been used for veterinary uses as an antiparasitic agent to treat flea and tick infestations in animals. Lotilaner consists of two enantiomers: the S-enantiomer is active in vivo, while the R-enantiomer is reported to exhibit low biological activity. The active ingredient found in drug products of lotilaner is the S-enantiomer. On July 25, 2023, lotilaner was approved by the FDA for the treatment of Demodex blepharitis, making it the first and only approved therapeutic for this condition.
Lotilaner is an Ectoparasiticide.
LOTILANER is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2017 and is indicated for eye infection and has 2 investigational indications.

Absorption, Distribution and Excretion
Following a single ocular dose, Tmax was approximately 2 hours after day 1; following the last dose, Tmax was approximately 1 hour after day 42. In healthy subjects, after 42 consecutive days of ocular administration, peak whole blood concentration (Cmax) increased from 0.596 ng/mL to 17.8 ng/mL. Total exposure (AUC0-12) also increased from 5.75 hr x ng/mL to 149 hr x ng/mL. In patients with Demodex blepharitis treated twice daily with loteranal for 42 days, the mean systemic exposure at the end of treatment was 12.0 ng/mL, ranging from 0.4 to 46.1 ng/mL.
No relevant information available.
No relevant information available.
No relevant information available.
Metabolism/Metabolites In cats, the metabolism of loteranal was not observed. Loteranal is not metabolized by CYP enzymes.

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Biological half-life
In healthy subjects, the effective half-life is 264 hours (11 days), calculated based on the cumulative ratio over a 12-hour dosing interval.

Protein Binding
Loteranar exhibits high plasma protein binding in human plasma (>99.9%). The distribution of loteranar in human blood cells is approximately 10% (range 0-20%).

[1]. The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls). Parasit Vectors. 2017 Nov 1;10(1):530.

Lotilaner belongs to the isoxazole class of compounds with the structure 4,5-dihydro-1,2-oxazole, substituted at positions 3, 5, and 6 with 4-methyl-5-({2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}carbamoyl)thiophene-2-yl, trifluoromethyl, and 3,4,5-trichlorophenyl (5S-stereoisomer). It is a GABA-gated chloride channel inhibitor with selectivity for mites and is approved for the treatment of Demodex blepharitis. It functions as a GABA-gated chloride channel antagonist, an ophthalmic agent, and an in vitro parasite killer. It is a trichlorobenzene and belongs to the isoxazole, organofluorine, thiophene, and secondary amide classes. Lotilaner is an in vitro parasite killer belonging to the isoxazoline class of compounds. Lotelanar is primarily used as a veterinary antiparasitic drug to treat flea and tick infections in animals. Lotelanar has two enantiomers: the S-enantiomer has in vivo activity, while the R-enantiomer has been reported to have lower biological activity. The active ingredient in lotelanar formulations is the S-enantiomer. On July 25, 2023, lotelanar was approved by the U.S. Food and Drug Administration (FDA) for the treatment of Demodex blepharitis, becoming the first and currently only approved drug for this condition. Lotelanar is an ectoparasitic agent.
Drug Indications
Lotelanar is indicated for the treatment of Demodex blepharitis. It can also be used to treat flea and tick infections. Fleas and ticks must attach to a host and begin feeding to access the active ingredient. This veterinary product can be used as part of a treatment regimen to control flea allergic dermatitis (FAD). Canines: This veterinary drug provides immediate and sustained killing of fleas (Ctenopharynx catii and Ctenopharynx dogii) and ticks (Herba Ursae Majoris, Herba Ricinus communis, Herba Hexagonae, and Herba Reticulatae), with effects lasting up to one month. Cats: This veterinary drug provides immediate and sustained killing of fleas (Ctenopharynx catii and Ctenopharynx dogii) and ticks (Herba Ricinus communis), with effects lasting up to one month. Mechanism of Action: Loteranar is a non-competitive γ-aminobutyric acid (GABA)-gated chloride channel (GABACl) antagonist with selectivity against mites. Inhibition of GABACl leads to paralysis of the target organism, ultimately resulting in death. In vitro studies showed that at concentrations up to 30 µM (18 µg/mL), loteranar was not a mammalian GABA-mediated chloride channel inhibitor, which is approximately 1100 times the recommended human ophthalmic dose. It is hypothesized that loteranal's target in GABACl lies within the pores between the T9' and S15' regions, which belong to the mesenchymal subunit region. One study suggests that loteranal may migrate to its final location within the GABACl pores, thereby stabilizing the channel in a closed state; however, this hypothesis requires further investigation.
Pharmacodynamics
Loteranal is an antiparasitic drug effective against Demodex mites that cause Demodex blepharitis. It is also effective against insects, ticks, and lice. Its activity is arthropod-specific because it does not bind to the same therapeutic targets in mammals.

C20H14CL3F6N3O3S

596.757881641388

594.973

C, 40.25; H, 2.36; Cl, 17.82; F, 19.10; N, 7.04; O, 8.04; S, 5.37

1369852-71-0

76959255

White to off-white solid powder

6.224

2

11

6

36

868

1

CC1=C(SC(=C1)C2=NO[C@@](C2)(C3=CC(=C(C(=C3)Cl)Cl)Cl)C(F)(F)F)C(=O)NCC(=O)NCC(F)(F)F

HDKWFBCPLKNOCK-SFHVURJKSA-N

InChI=1S/C20H14Cl3F6N3O3S/c1-8-2-13(36-16(8)17(34)30-6-14(33)31-7-19(24,25)26)12-5-18(35-32-12,20(27,28)29)9-3-10(21)15(23)11(22)4-9/h2-4H,5-7H2,1H3,(H,30,34)(H,31,33)/t18-/m0/s1

3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide

Lotilaner; 1369852-71-0; Credelio; XDEMVY; lotilanerum; Xdemvy

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ≥ 100 mg/mL (~167.57 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.19 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 25.0 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: ≥ 2.08 mg/mL (3.49 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 20.8 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.)