Chemistry Reference
In-Depth Information
Table 10.1 Antiviral activity of N(t)RTIs and comparision of RT inhibition
by N(t)RTI and NRTI
O
NH
2
NH
2
R
N
N
NH
N
N
OH
OH
HO
OH
HO
HO
P
O
N
P
O
N
P
O
O
N
O
N
N
O
O
O
O
O
16
12. R= Me
13. R = H
14. R = F
15
.
wt HIV
a
MT-2
EC
50
(mM)
wt RT
b
IC
50
(mM)
Nucleoside
c
wt
RT IC
50
(mM)
MT-2 cell
CC
50
(mM)
Compound
12 26 (8.8) 41000 0.39 (0.08) 0.06 (0.03)
13 4200 41000 5.7 0.55 (0.15)
14 4200 - - -
15 2.1 (1.0) 41000 0.60 (0.16) 0.14 (0.07)
16 12 (2.5) 41000 4.1 (1.8) 0.26 (0.14)
a
Values are results of at least two experiments; standard deviation is given in parentheses.
b
Data for the diphosphophosphonate metabolites.
c
Data for the equivalent nucleoside triphosphate analog with the same nucleoside core.
penetration and/or metabolism.
18,19
In general, adenine nucleoside phospho-
nates often show antiviral activity and appear to be more ecient at generating
the intracellular diphosphates than the pyrimidines, so further SAR was
focused toward adenine analogs. A second example is the saturated dideoxy
(dd) analog 16, which demonstrated reduced antiviral activity but on pre-
paration of the active diphosphate was shown to also have reduced potency
toward RT. Active site modeling in HIV RT provided a rationale for the
reduced potency since the double bond of the ribose ring in the d4 analogs is
positioned above the aryl ring of residue Tyr115, and likely gains binding
potency through favorable p-p stacking interactions.
19
Amongst several pairs
of dd and d4 N(t)RTI analogs with the same nucleobase, the unsaturated d4
analogs were always the more potent toward RT, a trend that was also con-
sistent in the nucleoside analogs also shown in Table 10.1. These observations
benefitted the program by providing greater confidence in the active-site models
for the N(t)RTIs, and also the ability to apply information from the extensive
nucleoside literature to future target design. A nice illustration of this came
during the course of the program when a literature report established that the
4
0
-ethynyl-modified analog 17, with the desirable d4 ribose core, had improved
antiviral activity compared to the 4
0
-unsubstituted analog, including K65R
hypersensitivity, one of the RT mutants of particular interest in the screening
panel (Table 10.2).
20
The RT active-site model indicated that a small pocket existed to accom-
modate the 4
0
-ethynyl group, leading to additional binding interactions. In
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