Chemistry Reference
In-Depth Information
TABLE 9-5. Structures and Anti-HIV Activities of DCK Analogs (95-106)
a
;
39
R
6
R
3
R
3
O
O
O
O
O
O
O
O
O
OR
OR
OR
OR
R = Camphanoyl
OR
OR
95-99
100-102
103-106
IC
50
(mM)
b
EC
50
(mM)
c
Therapeutic Index
d
Compound
95
R
3
¼
Br
>
11.1
0.059
>
186
96
R
3
¼
OAc
11.6
0.017
676
97
R
3
¼
OH
23.0
0.029
806
98
R
3
¼
NH
2
>
15.4
0.677
>
23
99
R
3
¼
NEt
2
>
14.1
3.67
>
4
100
R
3
¼
Br
>
20.9
0.00011
>
189,600
101
R
3
¼
OAc
14.8
0.026
567
102
R
3
¼
OH
24.9
0.0042
6,000
103
R
6
¼
Br
>
13.7
0.156
>
88
104
R
6
¼
OAc
>
14.1
0.544
>
26
105
R
6
¼
OH
>
15.0
0.111
>
135
106
R
6
¼
NH
2
>
15.0
0.148
>
102
DCK (2)
e
>
16.1
0.049
>
328
f
53
>
39.0
0.0059
>
6,600
a
All
data
presented
are
averages
of
at
least
two
separate
experiments
performed
by
Panacos
Pharmaceutical Inc.
b
Concentration that inhibits uninfected H9 cell growth by 50%.
c
Concentration that inhibits viral replication by 50%.
d
TI = IC
50
/EC
50
.
e
EC
50
¼
2
:
56
10
4
and TI
¼
1
:
37
10
5
in previous screenings and publication.
22
f
EC
50
¼
1
:
83
10
6
and TI
¼
6
:
89
10
7
in previous screenings and publication.
25
Because of a
systematic change of the Panacos screening method, we observed large differences in the results of
previously active compounds in the screening. All compounds in Table 9-5 were screened in the new
system, in parallel with DCK (2) and 4-methyl DCK (53).
In the assay against the non-drug-resistant strain, compounds 108 (3-methyl) and
111 (2-ethyl) exhibited extremely high anti-HIV activity with nanomolar EC
50
values (Table 9-6). Compounds 107 (DCP), 110 (2-methyl), and 116 (2,3-dimethyl)
also showed better anti-HIV activity than DCK (2). Analogs 112-115 with a bigger
2- or 3-substituent (propyl, isopropyl, ethoxymethyl or phenyl) were less potent.
Like the SAR of DCK analogs, 117 (6-t-butyl) lost almost all activity. A compar-
ison of 3
0
-O-acyl compounds 118-120 indicates that an isovaleryl at the C-3
0
seems
essential for high anti-HIV potency in H9 lymphocytes. The 2-phenyl analogs (123
and 124) showed weak activity. These data demonstrated that, in DCP analogs,
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