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H
H
OH
OH
H
H
O
O
H
H
RHN
RHN
H
H
O
O
276
R=
279
R=
COOH
COOH
O
O
277
R=
280
R=
COOH
COOH
O
O
278
R=
281
R=
O
COOH
O
COOH
Figure 9-13. 3-N-acyl-betulinc acid derivatives (276-281).
(273-275) showed only slight activity. Several compounds with C-28 ester substi-
tution and a free C-3 hydroxy or both C-3 and C-28 substituents did not exhibit high
potency.
69,85
DSB (263) showed potent inhibition against both wild-type and drug-
resistant HIV-1 isolates; therefore, it has been chosen as a drug candidate for the
treatment of AIDS. Panacos Inc. filed an IND application on DSB (so-called PA-457)
with the U.S. FDA in March 2004.
A series of 3-N-acyl-betulinc acid derivatives were synthesized to explore the
SAR. The structures of 3b-N-acyl-betulinc acid derivatives (276-278) and 3a-N-
acyl-betulinc acid analogs (279-281)areshowninFigure9-13.Noneofthemshowed
comparable activity with the corresponding 3b-O-acyl BA derivatives. Therefore, ami-
no-acyl substitution at position 3 is not favorable for anti-HIV activity.
86
9.4.2.2 Mechanism of Action of DSB
Although DSB (263) shares the BA skeleton of RPR103611 (246) and IC9564
(257), it does not target the HIV-1 entry process. Several targets for DSB were
ruled out, including viral attachment, RT, IN, and PR. A time-of-addition study sug-
gested that DSB blocks viral replication at a time point after the completion of viral
DNA integration and Tat expression. Virions mature late in the virus replication
cycle through cleavage of the Gag polyprotein by PR, which results in release of
the virion proteins matrix (MA), capsid (CA), nucleocapsid (NC), p6, and two
spacer peptides, SP1 and SP2.
87
Incomplete Gag processing, a ordered event,
88
results in virions that lack a functional core and are noninfectious.
89-91
Li et al.
observed abnormal Gag protein processing in a virus generated in the presence
of a compound. Radioimmunoprecipitation revealed analyses revealed that DSB
specifically inhibited the conversion of p25 (CA-SP1) to p24 (CA), the last step
of Gag processing, as increased levels of p25 were detected in both cell and virion
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