Optimization of isoxazoline amide benzoxaboroles for identification of a development candidate as an oral long acting animal ectoparasiticide
| Autor: | Jianzhang Yang, Joseph Raymond Winkle, Jacob J. Plattner, Yong-Kang Zhang, Zhixin Ge, Eric E. Easom, Jianxin Cao, Terry William Balko, Yasheen Zhou, Defauw Jean Marie, W. Hunter White, Tsutomu Akama |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Boron Compounds Stereochemistry Clinical Biochemistry Cmax Pharmaceutical Science Administration Oral Ectoparasitic Infestations Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Dogs Parasitic Sensitivity Tests Drug Discovery Animals Dermacentor variabilis Benzamide Molecular Biology Ctenocephalides Ectoparasiticide Dermacentor biology Antiparasitic Agents Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Isoxazoles biology.organism_classification Antiparasitic agent Amides 030104 developmental biology Pharmacodynamics Cats Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 26(13) |
| ISSN: | 1464-3405 |
| Popis: | Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.0h; terminal half-life t1/2=127h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24h of treatment, with residual efficacy of 97% against American dog ticks (Dermacentor variabilis) on day 30 and 98% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 25mg/kg in dogs. |
| Databáze: | OpenAIRE |
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