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O
H
H
N
*
COOH
H
N
H
O
OH
H
246 RPR 103611 (* S)
257 IC 9564 (* R)
HO
H
H
O
H
N
H
N
H
COOH
(CH
2
)
7
O
OH
H
HO
H
258
H
O
NH(CH
2
)m
H
N
H
COOR
O
H
259
m=7, R=H
260
m=7, R=CH
3
261
m=10, R=H
HO
H
Figure 9-12. Structures of RPR103611 (246), IC9564 (257), and 258-261.
IC9564 (257, Figure 9-12)
78
is an equipotent stereoisomer of 246. The results
confirmed that a free hydroxy group at C-3 and free carboxylic acid in the C-28
side chain are necessary for anti-HIV activity. The double bond of the isopropyli-
dene group might not play a key role in the HIV inhibitory activity of this com-
pound type, because 258 exhibited similar potency to 257. Replacing the statine
moiety of 257 with L-leucine yielded a four-fold less potent compound 259. Interest-
ingly, the methyl ester (260)of259 showed increased potency (EC
50
ΒΌ
0.52 mM).
Compound 261, with ten methylenes, showed three-fold greater activity than 259,
which has seven methylenes. These results indicate that the statine group in the
C-28 side chain of IC9564 (257) can be replaced by L-leucine and that the number
of methylenes in the aminoalkanoic chain is crucial to optimal anti-HIV potency.
9.4.1.4 Mechanism of Action
RPR103611 (246) was tested in a panel of isolates and cell lines, including the
monocytic cell line U-937 and peripheral blood lymphocytes. The IC
50
values
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