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M. Tomishima et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2886–2890
and a nitrile oxide.11 Biological evaluation of the deriv-
atives containing the novel five-membered heterocyclic
ring was performed, and results are summarized in Ta-
ble 2. As indicated in Table 2, thiazole 7, isoxazole 8,
isoxazole isomer 9, and thiadiazole 10 all displayed re-
duced hemolytic potential compared to the terphenyl
compound 3. In particular, compound 8 displayed po-
tent in vitro antifungal activity and low hemolytic po-
tential and was selected for further evaluation.
Acknowledgment
We thank Dr. David Barrett (Medicinal Chemistry Re-
search Laboratories) for kind help and advice.
Supplementary data
Representative synthetic procedure and spectrum data
for micafungin (8) and determination method for MICs
in mouse serum are available. Supplementary data asso-
ciated with this article can be found, in the online ver-
Table 3 indicates the in vivo antifungal effects of the se-
lected compounds (4, 8) against the principal fungal spe-
cies causing life-threatening infections in humans, C.
albicans and A. fumigatus, along with pharmacokinetic
(PK) data in mice. It can be clearly seen from the data
in this table that a more potent serum MIC (minimum
inhibitory concentration) gives superior in vivo efficacy
for C. albicans infections. As indicated in the earlier pa-
per2 FR131535 displays comparable in vivo efficacy to
fluconazole against C. albicans. Compounds 4 and 8
showed about 10 times superior in vivo efficacy com-
pared to FR131535. Against A. fumigatus systemic
infection, compound 8, in particular showed excellent
efficacy, displaying an ED50 value of 0.228 mg/kg. The
data in Table 3 suggest that the potent efficacy in the
Candida model results from the combination of good
serum MIC and a high AUC in the PK study, whereas
for good efficacy in the Aspergillus model, it is necessary
to have a good balance of MIC, elimination half-life.
Compound 8 was selected for further evaluation as a
clinical candidate.
References and notes
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In summary, further optimization of the acyl side chain
of a series of analogs of the water-soluble 1,3-b-glucan
synthase inhibitor FR901379 led to the discovery of an
analog (8) with potent in vivo activity against both C.
albicans and A. fumigatus. This analog (FK463, mica-
fungin) was selected as a clinical candidate and detailed
in vivo and clinical trial results have been disclosed. The
key to success was the introduction of various heterocy-
cles in place of the central phenyl ring of the terphenyl
analog 3 as such modifications resulted in potent anti-
fungal activity and significantly reduced hemolysis.