3024 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Communications to the Editor
Ta ble 1. Anti-HCMV Activity and Cytotoxicity of
1,6-Naphthyridines: Modification of Amine
the phenyl ring and the amide nitrogen is also impor-
tant for activity; while the benzyl analogue 22 is
moderately active, anilide 23 is devoid of any activity,
whereas a two-carbon linker as in phenethyl 25 provides
moderate activity which cannot be improved by intro-
duction of a 2-methoxy moiety (25).
Introduction of a methyl group at the 4-position
(compound 26) resulted in weak activity and a poor
selectivity index, whereas substitution at the 8-position
was in general beneficial (Table 2). Both halo derivatives
8 (Br) and 9 (Cl) show activity with the chloro analogue
being more potent and more selective. Introduction of
a carbon substituent had a dramatic effect on potency;
both the methyl and vinyl analogues were extremely
potent and selective. The vinyl derivative 10 had an IC50
of 3 ng/mL (IC90 of 0.25 µg/mL) and a selectivity index
of more than 5000, whereas the methyl analogue 11 was
even more potent with an IC50 of 0.4 ng/mL (IC90 of 0.09
µg/mL) and a selectivity index of greater than 7000.
Preliminary experiments have shown that this novel
class of HCMV inhibitors is not cross-resistant to GCV
and CDV; HCMV strains resistant to GCV (C8704 and
C8805-37, UL97 phosphotransferase mutants and D16,
UL54 DNA polymerase mutant)11 as well as to CDV
(1117r3-1-2, genotype unknown)11 are still sensitive to
17. In addition, since the naphthyridines and these
nucleoside analogues do not share any common struc-
tural features, the mode of action of this class of
inhibitors is presumed to be different.
a
b
compd
n
R
IC50 (µg/mL) CC50 (µg/mL)
1
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1
1
1
1
1
1
1
1
1
1
1
1
0
2
2
2′-OMe
3′-OMe
4′-OMe
2′-Br
3′-Br
4′-Br
2′-OiPr
2′-OtBu
2′-O(R)sBu
2′-O(S)sBu
3′-iOPr
H
0.3
2.1
12.5
100
50
100
50
>50
0.7
2.2
>10
10
0.005
0.04
0.003
0.03
3.6
2.5
4.4
0.1
3.1
8.4
1
71
50
5
17
12.5
H
H
50
0.78
6
0.3
2′-OMe
ganciclovir
a
Mean of duplicate values (SD < 15%); all experiments were
performed at least twice. Mean of triplicate values (SD < 15%).
b
Ta ble 2. Anti-HCMV Activity and Cytotoxicity of 4- and
8-Substituted 1,6-Naphthyridines
In summary, based on a lead from random screening,
we have identified and synthesized a novel class of
HCMV inhibitors.12 We have defined the structural
requirements for potency and selectivity; our SAR
investigation suggests that an isopropoxy group at the
ortho position and substitution at C-8 are highly desir-
able. Some of the compounds described, such as 10, 11,
and 17, exhibit high potency and have an excellent
selectivity index. Further SAR studies as well as
mechanistic and pharmacokinetic studies on this class
of compounds are ongoing and will be reported in due
course.
a
b
compd
R1
R2
R3
IC50 (µg/mL) CC50 (µg/mL)
26
8
9
10
11
OMe Me
H
Br
Cl
Vinyl
Me
11
0.15
0.03
0.003
0.0004
0.3
8
9
6
OiPr
OiPr
OiPr
OiPr
H
H
H
H
17
3
12.5
ganciclovir
a
Mean of duplicate values (SD < 15%); all experiments were
performed at least twice. Mean of triplicate values (SD < 15%).
b
Tables 1 and 2.10 Table 1 summarizes the optimization
study of the amine portion of the molecule; it is apparent
that a 2-substituted benzylamine confers the best
potency to this class of compound. There is a distinct
preference in the methoxy, bromo, and isopropoxy cases
(compounds 1, 14, 17) for ortho substitution. While the
meta analogues (12, 15, 21) retain some activity, the
para isomers (13, 16) in the methoxy and bromo cases
are devoid of anti-HCMV activity. In addition, there is
a preference for a bulkier alkoxy group at the ortho
position, the isopropoxy analogue 17 is about 100-fold
more potent than methoxy analogue 1 with an IC50 of 5
ng/mL (IC90 of 0.06 µg/mL) and a selectivity index of
500. Further increasing the size to a sec-butoxy group
did not result in any appreciable improvement. The R
enantiomer 19 which is about 10-fold more active than
the S enantiomer 20 is almost equipotent to the isopro-
poxy 17 but has a lower selectivity index. The tert-
butoxy derivative 18 is 10-fold less active than the
isopropoxy analogue 17, indicating a preference for a
secondary alkoxy group. The 3-methoxy analogue 12
had a better selectivity index than the 2-methoxy 1, but
potency could not be increased by changing to the
bulkier 3-isopropoxy 21. Finally, the distance between
Ack n ow led gm en t. We wish to thank Mr. Alex
Cimpoia from Process and Development for preparation
of 4 and Ms. Lyne Marcil for assistance in the prepara-
tion of this manuscript.
Refer en ces
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Gazzard, B.; Griffiths, P. D.; J abs, D. A.; Kern, A. R.; Spector,
S. A. Summary of the II International Symposium on Cytome-
galovirus. Antiviral Res. 1998, 39, 141-162. (b) de J ong, M. D.;
Boucher, C. A. B.; Danner, S. A.; Gazzard, B.; Griffiths, P. D.;
Katlama, C.; Lange, J . M. A.; Richman, D. D.; Vella, S. Summary
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(4) Peakdale Fine Chemicals Ltd., Glossop Derbyshire, U.K.
(5) Carboxylic acid 4 is also available from Peakdale Fine Chemicals;
however, in-house preparation was more economical.