title: Optimization of isoxazoline amide benzoxaboroles for identification of a development candidate as an oral long acting animal ectoparasiticide.
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 (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.
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Easom
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Akama
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Elanco Animal Health Research and Development, A Division of Eli Lilly & Company, 2500 Innovation Way, Greenfield, IN 46140, USA.
authors.forename: W Hunter
authors.initials: WH
authors.lastname: White
authors.affiliation: Elanco Animal Health Research and Development, A Division of Eli Lilly & Company, 2500 Innovation Way, Greenfield, IN 46140, USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Defauw
authors.affiliation: Elanco Animal Health Research and Development, A Division of Eli Lilly & Company, 2500 Innovation Way, Greenfield, IN 46140, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Winkle
authors.affiliation: Elanco Animal Health Research and Development, A Division of Eli Lilly & Company, 2500 Innovation Way, Greenfield, IN 46140, USA.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Balko
authors.affiliation: Shanghai ChemPartner, 998 Halei Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Cao
authors.affiliation: Shanghai ChemPartner, 998 Halei Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Sundia MediTech Company, Ltd, Building 8, 388 Jialilue Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
authors.forename: Jianzhang
authors.initials: J
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002415:Cats; D058251:Ctenocephalides / Q000187:drug effects*; D003870:Dermacentor / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004478:Ectoparasitic Infestations / Q000188:drug therapy* / Q000469:parasitology; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000977:Antiparasitic Agents; D001896:Boron Compounds; D007555:Isoxazoles
keywords: Benzoxaborole; Ectoparasiticide; Isoxazoline; Structure–activity relationship; Tick and flea