Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis.
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.
Nare
Bakela
B
Scynexis, Inc, Research Triangle Park, North Carolina 27713, USA. bakela.nare@scynexis.com
Wring
Stephen
S
Bacchi
Cyrus
C
Beaudet
Beth
B
Bowling
Tana
T
Brun
Reto
R
Chen
Daitao
D
Ding
Charles
C
Freund
Yvonne
Y
Gaukel
Eric
E
Hussain
Ali
A
Jarnagin
Kurt
K
Jenks
Matthew
M
Kaiser
Marcel
M
Mercer
Luke
L
Mejia
Elena
E
Noe
Andy
A
Orr
Matt
M
Parham
Robin
R
Plattner
Jacob
J
Randolph
Ryan
R
Rattendi
Donna
D
Rewerts
Cindy
C
Sligar
Jessica
J
Yarlett
Nigel
N
Don
Robert
R
Jacobs
Robert
R
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*
D007093:Imidazoles; D014344:Trypanocidal Agents