Jean Marie Defauw

Discovery of an orally bioavailable isoxazoline benzoxaborole (AN8030) as a long acting animal ectoparasiticide

A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs.

Potent and selective PKC inhibitory 5-membered ring analogs of balanol with replacement of the carboxamide moiety

Balanol ((−)-1) is a potent protein kinase inhibitory natural product isolated from the fungus Verticillium balanoides. The lack of cellular activity and protein kinase C selectivity in balanol has prompted a search for analogs that incorporate these properties. This paper describes the synthesis and biological activity of such compounds with substitution similar to balanol, but with a single atom bridge in place of the carboxamide moiety.

NOVEL PKC INHIBITORY ANALOGS OF BALANOL WITH REPLACEMENT OF THE ESTER FUNCTIONALITY

Abstract Balanol ((−)-1) is a potent protein kinase inhibitory natural product isolated from the fungus Verticillium balanoides . The presence of an ester functionality in this molecule has prompted concern over the metabolic stability of balanol, and has led to a search for active analogs lacking this moiety. The synthesis and serum stability for some of these is presented herein.

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

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.