survival at 12.5 and 6.25 mpk, respectively. Mean survival time
at these doses was nearly identical for 10q and 10ag, but at 3.125
mpk, 10q achieved 30% survival with a mean survival time of 10.7
days versus 10% and 7.3 days for 10ag. Compound 10ac
demonstrated exceptional efficacy with 90% survival at both 12.5
and 6.25 mpk with mean survival of over 19 days. The efficacy of
10ac fell precipitously with only 20% survival at 3.125 mpk,
though the mean survival time (12.2 days) was longer than 10q or
10ag. At the 1.56 mpk dose, 100% mortality was observed for all
three analogs with only a 1-2 day extension in mean survival time.
The higher survival rates observed for 10ac translated into 2-3X
improvements in ED50 (effective dose for 50% survival) and ED90
(effective dose for 90% survival) relative to 10q and 10ag.
Due to its superior efficacy in the aspergillosis survival
compound (MK-3118, SCY-078, ibrexafungerp). Owing to its
improved efficacy profile in the 7-day TOKA and aspergillosis
survival model, the clinical development of ibrexafungerp was
prioritized over MK-5204. Having progressed to phase III clinical
trials, ibrexafungerp has the potential to become an important
antifungal therapy with benefits over existing options due to its
oral efficacy and broad spectrum antifungal activity, which
includes echinocandin resistant isolates and Candida auris.
Acknowledgements
The authors wish to thank Dr. Ashok Arasappan, Dr. Jason Cox,
and Ms. Helen Chen for their helpful suggestions in the
preparation of this manuscript.
model, antifungal susceptibility testing against additional fungal
species was performed with 10ac to determine its spectrum of
activity (Table 5). Compound 10ac demonstrated antifungal
activity against the clinically relevant yeast and mold species
displayed in Table 5. Higher concentrations of 10ac were required
to achieve complete inhibition of growth (MIC-100) for Candida
krusei and Candida tropicalis, though prominent inhibition (MIC-
50) was observed at 2-8 fold lower concentrations. Testing against
expanded panels of Candida (113 isolates) and Aspergillus (71
isolates) species further established 10ac as a potent, broad
spectrum antifungal.34-35 Additional studies demonstrated that
10ac is active against a majority of echinocandin resistant Candida
and Aspergillus isolates as well as the recently emerging multi-
drug resistant Candida auris.36-38
Appendix A – Supplemental Data
Supplementary data for this article can be found online at…
References and notes
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Table 5
Extended antifungal activity spectrum of 10ac
Antifungal activity of 10ac verses Candida and Aspergillus species
Species
MIC-100a μg/mL
MIC-50b μg/mL
C. albicans (MY1055)
(+50% mouse serum)
C. glabrata (MY1381)
C. krusei (ATCC6258)
C. tropicalis (MY1012)
C. lusitaniae (MY1396)
C. parapsilosis (ATTC22109)
Species
0.06
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4
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2
0.5
1
<0.03
MEC μg/mL
A. fumigatus (MF5668)
(+50% human serum)
<0.03
0.25
aLowest concentration of compound to completely inhibit fungal growth.
bLowest concentration of compound to restrict fungal growth by 50%.
In conclusion, a scan of 3-alkyl and aryl-2-[1,2,4-
triazole] substituents identified 3-(4-pyridyl)-2-[1,2,4-triazole] as
the optimal replacement for the 3-carboxamide-2-[1,2,4-triazole]
substituent of MK-5204 (3).19 The 4-pyridyl substituent of 10q
((R) isopropyl, methyl aminoether) produced
a
4-fold
improvement in antifungal activity in the presence of serum
relative to 3 in conjunction with a 1.5X increase in oral exposure.
Re-optimization of the alkyl substituents alpha to the amine of the
C3 aminoether in the presence of the 3-(4-pyridyl)-2-[1,2,4-
triazole] substituent at C2, established (R) t-butyl, methyl (10ac)
as the preferred C3 aminoether with a 2X increase in oral exposure
over 3, while maintaining the 4-fold improvement in antifungal
activity in the presence of serum observed for 10q. The concurrent
improvements in these two parameters, which had previously
correlated with oral efficacy, resulted in a drastic improvement in
the 7-day TOKA ED99 for 10ac (0.84 mpk) relative to MK-5204
(3) (6.4 mpk).19 Compound 10q demonstrated similar efficacy to
10ac in the 7-day TOKA, but 10ac displayed superior efficacy in
the aspergillosis survival model and exhibited a favorable rhesus
PK profile compared to 10q. As a result of these advantages and
its broad spectrum of antifungal activity for Candida and
Aspergillus species, 10ac was selected as the development
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