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5271
A series of analogs with the amino group were then explored
(Table 3). The aniline moiety was found to tolerate small substitu-
ents such as F, Cl, Me and OMe. However, larger substituents such as
OCF3, iPr, and CONH2 were found to decrease the antifungal potency
significantly. Although most aniline analogs displayed a much
improved plasma exposure, substitution directly on the aniline
nitrogen (analogs 11k and 11l) led to compounds that retained po-
tency, but provided no measurable exposure after oral dosing. Ami-
nopyridine analogs (11m–o, clogP 2.9) exhibit slightly decreased
activity, and their PK profiles were no better than the aniline
analogs.
with glucan synthase inhibitors such as the echinocandins.5 This
supports the hypothesis that the antifungal activity of this class
of compounds acts through the inhibition of glucan synthase.
In conclusion, a novel series of GS inhibitors has been discov-
ered. Optimization of both the antifungal activity and PK profiles
has led to the identification of compound 11g which exhibits
in vivo efficacy ip in a lethal fungal infection model. Further explo-
ration of this class of compounds as antifungal agents will be
reported in due course.
References and notes
Compound 11g gave high blood levels in both rat and mouse,
1. Moudgal, V.; Sobel, J. Expert Opin. Pharmacother. 2010, 11, 2037.
2. Kitamura, A. Expert Opin. Drug Discov. 2010, 5, 739.
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and was highly potent against Candida albicans C697 (MIC100
=
0.13 g/mL). This compound was selected for evaluation in a lethal
l
infection model. Normal mice and immune compromised mice
were separately infected with C. albicans C697 (5 Â 107 CFU/
mouse) and subsequently treated with 100 mg/kg (ip) compound
11g, (maleate), 5 mg/kg (ip) caspofungin or vehicle (ip) daily.
Survival was monitored for 4 days. Both 11g and caspofungin pro-
duced 100% survival in normal mice and in immune compromised
mice infected with C. albicans C697 for the duration of the study. In
addition, all treated mice showed significant reductions in fungal
kidney burdens.
For the current series of pyridazine-based GS inhibitors, their
cell-based antifungal activity (MIC) correlates well with their en-
zyme glucan synthase inhibitory activity (IC50). Furthermore, for
filamentous fungi such as Aspergillus fumigatus, 11g caused a dis-
tinct morphological response characterized by substantially trun-
cated and highly branched hyphae, as has been typically seen
4. (a) Ting, P. C.; Kuang, R.; Wu, H.; Aslanian, R. G.; Cao, J.; Kim, D. W.; Lee, J. F.;
Schwerdt, J.; Zhou, G.; Wainhaus, S.; Black, T. A.; Cacciapuoti, A.; McNicholas, P.
M.; Xu, Y.; Walker, S. S. Bioorg. Med. Chem. Lett. 1819, 2011, 21; (b) Zhou, G.; Ting,
P. C.; Aslanian, R.; Cao, J.; Kim, D. W.; Kuang, R.; Lee, J. F.; Schwerdt, J.; Wu, H.;
Herr, R. J.; Zych, A. J.; Yang, J.; Lam, S. Q.; Wainhaus, S.; Black, T. A.; McNicholas,
P. M.; Xu, Y.; Walker, S. S. Bioorg. Med. Chem. Lett. 2011, 21, 2890.
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Mann, P.; Chau, A.; Patel, R.; Bauman, N.; Norris, C.; Antonacci, B.; Gurnani, M.;
Cacchiapuoti, A.; McNicholas, P. M.; Wainhaus, S.; Herr, R. J.; Kuang, R.; Aslanian,
R. G.; Ting, P. C.; Black, T. A. Antimicrob. Agents Chemother. 2011, 55, 5099.
6. Ting, P. C.; Aslanian, R. G.; Cao, J.; Kim, D. W.; Kuang, R.; Zhou, G.; Herr, R. J.;
Zych, A. J.; Yang, J.; Wu, H.; Zorn, N. World Patent 2008115381, 2008.
7. Antimicrobial susceptibility testing was carried out in accordance with the
Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts;
Approved Standard—Third Edition (M27-A3). Published by The Clinical and
Laboratory Standards Institute. 2008. All fungi used in these studies are from the
Schering-Plough strain collection.