Optimization of isoxazoline amide benzoxaboroles for identification of a development candidate as an oral long acting animal ectoparasiticide

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• 作者：Yong-Kang Zhang^a ; ; Jacob J. Plattner^a ; Eric E. Easom^a ; Tsutomu Akama^a ; Yasheen Zhou^a ; W. Hunter White^b ; Jean M. Defauw^b ; Joseph R. Winkle^b ; Terry W. Balko^b ; Jianxin Cao^c ; Zhixin Ge^c ; Jianzhang Yang^d
• 关键词：Benzoxaborole ; Isoxazoline ; Structure&ndash ; activity relationship ; Ectoparasiticide ; Tick and flea
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：26
• 期：13
• 页码：3182-3186
• 全文大小：773 K

文摘

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 (C_max = 7.42 ng/mL; T_max = 26.0 h; terminal half-life t_1/2 = 127 h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24 h 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 25 mg/kg in dogs.