Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system African trypanosomiasis

Nare, Bakela, Wring, Stephen, Bacchi, Cyrus, Beaudet, Beth, Bowling, Tana, Brun, Reto, Chen, Daitao, Ding, Charles, Freund, Yvonne, Gaukel, Eric, Hussain, Ali, Jarnagin, Kurt, Jenks, Matthew, Kaiser, Marcel, Mercer, Luke, Mejia, Elena, Noe, Andy, Orr, Matt, Parham, Robin, Plattner, Jacob, Randolph, Ryan, Rattendi, Donna, Rewerts, Cindy, Sligar, Jacob, Yarlett, Nigel, Don, Robert and Jacobs, Robert (2010) Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system African trypanosomiasis. Antimicrobial Agents and Chemotherapy, 54 10: 4379-4388. doi:10.1128/AAC.00498-10

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Author Nare, Bakela
Wring, Stephen
Bacchi, Cyrus
Beaudet, Beth
Bowling, Tana
Brun, Reto
Chen, Daitao
Ding, Charles
Freund, Yvonne
Gaukel, Eric
Hussain, Ali
Jarnagin, Kurt
Jenks, Matthew
Kaiser, Marcel
Mercer, Luke
Mejia, Elena
Noe, Andy
Orr, Matt
Parham, Robin
Plattner, Jacob
Randolph, Ryan
Rattendi, Donna
Rewerts, Cindy
Sligar, Jacob
Yarlett, Nigel
Don, Robert
Jacobs, Robert
Title Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system African trypanosomiasis
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2010-10
Sub-type Article (original research)
DOI 10.1128/AAC.00498-10
Open Access Status File (Publisher version)
Volume 54
Issue 10
Start page 4379
End page 4388
Total pages 10
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2013
Language eng
Formatted 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.
Keyword African trypanosomiasis
Animal model
Antiprotozoal activity
In vitro
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Centre for Integrated Preclinical Drug Development Publications
 
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Created: Thu, 08 Mar 2012, 09:47:07 EST by Ian Sawyer on behalf of Centre for Integrated Preclinical Drug Development