title: SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis.
abstract: BACKGROUND
  Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT.
  
  
  RESULTS
  A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C(max) >10 µg/mL and AUC(0-24 hr) >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment.
  
  
  CONCLUSIONS
  The biological and pharmacokinetic properties of SCYX-7158 suggest that this compound will be efficacious and safe to treat stage 2 HAT. SCYX-7158 has been selected to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011.
authors: SCYNEXIS, Inc., Research Triangle Park, North Carolina, USA. bob.jacobs@scynexis.com
authors: Robert T
authors: RT
authors: Jacobs
authors: Bakela
authors: B
authors: Nare
authors: Stephen A
authors: SA
authors: Wring
authors: Matthew D
authors: MD
authors: Orr
authors: Daitao
authors: D
authors: Chen
authors: Jessica M
authors: JM
authors: Sligar
authors: Matthew X
authors: MX
authors: Jenks
authors: Robert A
authors: RA
authors: Noe
authors: Tana S
authors: TS
authors: Bowling
authors: Luke T
authors: LT
authors: Mercer
authors: Cindy
authors: C
authors: Rewerts
authors: Eric
authors: E
authors: Gaukel
authors: Jennifer
authors: J
authors: Owens
authors: Robin
authors: R
authors: Parham
authors: Ryan
authors: R
authors: Randolph
authors: Beth
authors: B
authors: Beaudet
authors: Cyrus J
authors: CJ
authors: Bacchi
authors: Nigel
authors: N
authors: Yarlett
authors: Jacob J
authors: JJ
authors: Plattner
authors: Yvonne
authors: Y
authors: Freund
authors: Charles
authors: C
authors: Ding
authors: Tsutomu
authors: T
authors: Akama
authors: Y-K
authors: YK
authors: Zhang
authors: Reto
authors: R
authors: Brun
authors: Marcel
authors: M
authors: Kaiser
authors: Ivan
authors: I
authors: Scandale
authors: Robert
authors: R
authors: Don
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001896:Boron Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D021261:Parasitic Sensitivity Tests; D018419:Primate Diseases / Q000188:drug therapy; D011323:Primates; D012376:Rodent Diseases / Q000188:drug therapy; D016896:Treatment Outcome; D014345:Trypanosoma / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D001549:Benzamides; D001896:Boron Compounds; C557508:SCYX 7158