DNDI-6148: A Novel
Benzoxaborole Preclinical Candidate
for the Treatment of Visceral Leishmaniasis
Posted on 2021-10-29 - 06:04
Visceral leishmaniasis
(VL) is a parasitic disease endemic across
multiple regions of the world and is fatal if untreated. Current therapies
are unsuitable, and there is an urgent need for safe, short-course,
and low-cost oral treatments to combat this neglected disease. The
benzoxaborole chemotype has previously delivered clinical candidates
for the treatment of other parasitic diseases. Here, we describe the
development and optimization of this series, leading to the identification
of compounds with potent in vitro and in
vivo antileishmanial activity. The lead compound (DNDI-6148)
combines impressive in vivo efficacy (>98% reduction
in parasite burden) with pharmaceutical properties suitable for onward
development and an acceptable safety profile. Detailed mode of action
studies confirm that DNDI-6148 acts principally through the inhibition
of Leishmania cleavage and polyadenylation specificity
factor (CPSF3) endonuclease. As a result of these studies and its
promising profile, DNDI-6148 has been declared a preclinical candidate
for the treatment of VL.
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Mowbray, Charles E.; Braillard, Stéphanie; Glossop, Paul A.; Whitlock, Gavin A.; Jacobs, Robert T.; Speake, Jason; et al. (2021). DNDI-6148: A Novel
Benzoxaborole Preclinical Candidate
for the Treatment of Visceral Leishmaniasis. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.1c01437
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AUTHORS (22)
CM
Charles E. Mowbray
SB
Stéphanie Braillard
PG
Paul A. Glossop
GW
Gavin A. Whitlock
RJ
Robert T. Jacobs
JS
Jason Speake
BP
Bharathi Pandi
BN
Bakela Nare
LM
Louis Maes
VY
Vanessa Yardley
YF
Yvonne Freund
RW
Richard J. Wall
SC
Sandra Carvalho
DB
Davide Bello
MV
Magali Van den Kerkhof
GC
Guy Caljon
IG
Ian H. Gilbert
VC
Victoriano Corpas-Lopez
IL
Iva Lukac
SP
Stephen Patterson
KEYWORDS
polyadenylation specificity factorpharmaceutical properties suitableefficacy (> 98cost oral treatmentsacceptable safety profileaction studies confirm6148 acts principallypromising profilevivo vitro urgent needpreclinical candidateparasitic diseasesparasite burdenneglected diseaseleishmania lead compounddetailed modecurrent therapiescombines impressivebenzoxaborole chemotypeantileishmanial activity