title: Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis.
abstract: We report the discovery of novel boron-containing molecules, exemplified by N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (AN3520) and 4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds against Trypanosoma brucei in vitro, including the two subspecies responsible for human disease T. b. rhodesiense and T. b. gambiense. These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to 10 mg/kg of body weight for 4 consecutive days. In stage 2 disease (central nervous system [CNS] involvement), mice infected with T. b. brucei were cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole-treated animals did not exhibit gross signs of compound-related acute or subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman primates, demonstrate that both SCYX-6759 and AN3520 are low-clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated the ability to cross the blood-brain barrier with no evidence of interaction with the P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against all T. brucei subspecies, excellent physicochemical profiles, in vitro metabolic stability, a low potential for CYP450 inhibition, a lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for the development of new and effective orally administered treatments for human African trypanosomiasis.
authors.affiliation: Scynexis, Inc, Research Triangle Park, North Carolina 27713, USA. bakela.nare@scynexis.com
authors.forename: Bakela
authors.initials: B
authors.lastname: Nare
authors.forename: Stephen
authors.initials: S
authors.lastname: Wring
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bacchi
authors.forename: Beth
authors.initials: B
authors.lastname: Beaudet
authors.forename: Tana
authors.initials: T
authors.lastname: Bowling
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Daitao
authors.initials: D
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Ding
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Freund
authors.forename: Eric
authors.initials: E
authors.lastname: Gaukel
authors.forename: Ali
authors.initials: A
authors.lastname: Hussain
authors.forename: Kurt
authors.initials: K
authors.lastname: Jarnagin
authors.forename: Matthew
authors.initials: M
authors.lastname: Jenks
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Luke
authors.initials: L
authors.lastname: Mercer
authors.forename: Elena
authors.initials: E
authors.lastname: Mejia
authors.forename: Andy
authors.initials: A
authors.lastname: Noe
authors.forename: Matt
authors.initials: M
authors.lastname: Orr
authors.forename: Robin
authors.initials: R
authors.lastname: Parham
authors.forename: Jacob
authors.initials: J
authors.lastname: Plattner
authors.forename: Ryan
authors.initials: R
authors.lastname: Randolph
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Cindy
authors.initials: C
authors.lastname: Rewerts
authors.forename: Jessica
authors.initials: J
authors.lastname: Sligar
authors.forename: Nigel
authors.initials: N
authors.lastname: Yarlett
authors.forename: Robert
authors.initials: R
authors.lastname: Don
authors.forename: Robert
authors.initials: R
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000472:pathogenicity*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D007093:Imidazoles; D014344:Trypanocidal Agents