CAS:	1093861-60-9
MF:	C26H17ClF9N3O3
MW:	625.87
EINECS:
Product Categories:	1;APIs;API;1093861-60-9
Mol File:	1093861-60-9.mol

Description	Afoxolaner is an insecticide and acaricide belonging to the isoxazoline family. Afoxolaner acts at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA), thereby blocking pre- and post-synaptic transfer of chloride ions across cell membranes.
Uses	Afoxolaner (brand name NexGard?) is used to treat and control flea and tick infestations in dogs. After being ingested by a dog, afoxolaner is distributed throughout the dog's body. When fleas or ticks bite the dog, they are exposed to the drug and killed during their blood meal.
Definition	Afoxolaner is used to treat and control flea and tick infestations in dogs. After being ingested by a dog, afoxolaner is distributed throughout the dog’s body. When fleas or ticks bite the dog, they are exposed to the drug and killed during their blood meal.
Pharmacokinetics	Afoxolaner orally administered to dogs was rapidly absorbed into blood. Max. blood levels were reached 2 to 12 hours after administration. Mean half-life in blood ranged from 7.7 to 17.8 days. Bioavailability was estimated to be approx. 74%. Half-life was higher in Collies than in Beagles, but no serious adverse effects were observed after treatment of Collies at 25 mg/kg bw (i.e. ~10x the therapeutic dose).Absorbed afoxolaner binds strongly (>99%) to blood proteins but it seems not to cause displacement of other drugs with high protein binding capacities.In dogs afoxolaner is slowly broken down into various metabolites, the major ones being a hydroxylate and a glucuronide. Elimination of both the metabolites and the parent compound occurrs mainly via biliary excretion and to a lesser extent through urine.
Synthesis	The synthesis of afoxolaner is as follows: Add to the 100ml reaction flaskIntermediate 4 (8.57g), HBTU (8.65g, 22.38mmol), DMF (20ml),Intermediate 5, mix well and add triethylamine. Make the pH of the mixed liquid system=10,Stir at room temperature for 40 minutes, TLC monitors the progress of the reaction,After full reaction,Add 40ml of water, stir and crystallize,Suction filtration, wash the filter cake with 20ml water,Dry the filter cake under reduced pressure,Then use a mixture of ethyl acetate and petroleum ether(1:2) or ethanol and water (1:2)The mixture is recrystallized,The white powder product Aphrana 1-2, (8.10g, yield 77%, purity 99.47%) was obtained.
Enzyme inhibitor	This orally active isoxazoline-based pesticide (FW = 901.18 g/mol; CAS 1093861-60-9; IUPAC Name: 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]- 4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl) amino]ethyl]-1-naphthalenecarboxamide, is highly active against fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis) in dogs. Afoxolaner is more potent, when tested in vitro, than any other compound ever tested in the membrane feeding system, including the avermectins. At an oral dose of 2.5 mg/kg, afoxolaner reaches pharmacologically effective plasma concentrations (0.1–0.2 μg/mL), blocking native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild-type channels as well as channelspossessing the dieldrin resistance-conferring Alanine-302-Serine mutation. Lack of cyclodiene cross-resistance for afoxolaner suggests that afoxolaner blocks GABA-gated chloride channels by binding at a site topologically distinct from the cyclodienes.
Metabolism	Afoxolaner is an isoxazoline compound. It works by blocking the transmissions of neuronal signals in insects. They do this by binding to chloride channels in nerve and muscle cells, causing the receptors to stop working. This in turn paralyses the parasites and kills them.Afoxolaner toxicity to fleas ensures that they die within 24 hours of it being administered. But the dog is unaffected, due to the specific selective nature of the drug.
Mode of action	Afoxolaner (the active ingredient of NEXGARD) and other isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.This mechanism exists not only in insects but also in mammals and other vertebrates. However the binding affinity of afoxolaner to GABA receptors of invertebrates is much higher than to GABA receptors in vertebrates. For this reason it is significantly less toxic to mammals than to insects and other pests.
References	Efficacy of afoxolaner (NexGard?) against natural infestations with Trichodectes canis in dogs under field conditions DOI:10.1186/s13071-022-05428-y Safety of oral afoxolaner formulated with or without milbemycin oxime in homozygous MDR1‐deficient collie dogs DOI:10.1111/jvp.13064 https://www.ema.europa.eu/en/documents/product-information/nexgard-epar-product-information_en.pdf MADISON BIOMEDICAL TECH CHENGDU - CN112457267, 2021, A The Inhibitor Index: A Desk Reference on Enzyme Inhibitors, Receptor Antagonists, Drugs, Toxins, Poisons, Biologics, and Therapeutic Leads DOI:10.1201/9781315184289 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a668d223-47a3-46b7-b642-f2de0dca6ab5

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Hebei Mojin Biotechnology Co., Ltd, Our company is a professional in 4'-Methylacetophenone,Levamisole hydrochloride ,N-Methylformamide and other chemical reagents research and development production enterprises. Our business covers more than 30 countries, most of the big customers come from Europe, America and other countries in the world, we can guarantee the quality and price. In recent decades, with the efforts of all employees, we have established many cooperative companies in shandong, henan, guangdong and other places. Our corporate purpose is based on the market, enhance the strength, take the road of scientific and environmental sustainable development, relying on the country. Technology r & d center, increase the investment in r & d, based on the domestic market, expand the international market, manufacturing quality products, sincere service to the society, into a modern, ecological, scientific and technological enterprise world.

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