Optimization of isoxazoline amide benzoxaboroles for identification of a development candidate as an oral long acting animal ectoparasiticide. Issue 13 (1st July 2016)

• Record Type: Journal Article
• Authors: Zhang, Yong-Kang; Plattner, Jacob J.; Easom, Eric E.; Akama, Tsutomu; Zhou, Yasheen; White, W. Hunter; Defauw, Jean M.; Winkle, Joseph R.; Balko, Terry W.; Cao, Jianxin; Ge, Zhixin; Yang, Jianzhang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 13(2016)
• Page Start: 3182
• Page End: 3186
• Publication Date: 2016-07-01
• Subjects: Benzoxaborole -- Isoxazoline -- Structure–activity relationship -- Ectoparasiticide -- Tick and flea; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.093
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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). Compound23, 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. Abstract: 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). Compound23, 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.