The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 1: Establishing the pharmacophore

Article abstract of DOI:10.1016/j.bmcl.2009.01.090

A series of HIV-1 integrase inhibitors containing a novel metal binding motif consisting of the 8-hydroxy-1,6-naphthyridine core and either an oxadiazole or triazole has been identified. The design of the key structural components was based on a two-metal

Full text of DOI:10.1016/j.bmcl.2009.01.090

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1802–1806
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The use of oxadiazole and triazole substituted naphthyridines as HIV-1
integrase inhibitors. Part 1: Establishing the pharmacophore
a
a
a
b
Brian A. Johns a, , Jason G. Weatherhead , Scott H. Allen , James B. Thompson , Edward P. Garvey ,
*
Scott A. Foster b, Jerry L. Jeffrey b, Wayne H. Miller b
a Department of Medicinal Chemistry, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709, USA
b Department of Virology, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park,
NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of HIV-1 integrase inhibitors containing a novel metal binding motif consisting of the 8-hydroxy-
1,6-naphthyridine core and either an oxadiazole or triazole has been identified. The design of the key
structural components was based on a two-metal coordination pharmacophore. This report presents ini-
tial structure–activity data that shows the new chelation architecture delivers potent inhibition in both
enzymatic and antiviral assays.
Received 10 December 2008
Accepted 15 January 2009
Available online 30 January 2009
Keywords:
HIV integrase
Integration
Ó 2009 Elsevier Ltd. All rights reserved.
Two-metal binder
Metal chelation
The advent of HAART therapy for the treatment of HIV infection
over a decade ago has transformed the lives of scores of patients dur-
ing that period.1 This treatment was based on typically a triple com-
bination of antiviral drugs resulting in numerous options for the
patient. However, with allthesuccessof HAART itneedstobe stressed
that the majority of treatment options have relied on two target en-
zymes, namely reverse transcriptase and protease. The development
of fusion and entry inhibitors more recently have also had an impact
but their role is yet to be completely appreciated by patients as a re-
sult of dosing regimen and tropism concerns, respectively, along with
theirrelativelyrecentintroduction.2 Thethirdandonlyremainingvir-
al enzyme, integrase, has been slower to succumb to drug discovery
effortsbut afternearly20 years of study thefirst antiviral agentutiliz-
ing integrase inhibition as its mechanism of action (raltegravir) was
approvedinlate2007.3,4 Itseemsclearthataccessbypatientstodrugs
with novel mechanisms of inhibiting the virus are going to again shift
the paradigm of treatment options for HIV infected individuals.5
While the clinical data and market excitement for raltegravir is very
encouraging, itwouldbenaïve tothink that oneagent inthisclasswill
suffice to meet patient medical needs in the long term. Therefore new
agents within this class are needed and the search for potent and or-
ally bioavailable inhibitors of HIV-1 integrase is currently one of the
most active areas of antiviral research.
alyze
a
phosphodiester cleavage/formation sequence to
incorporate viral double-stranded DNA into host chromatin. This
enzymatic process is dependent on an active site containing dual
Mg2+ metal ions held in place with a highly conserved triad of car-
boxylate amino acid residues (asp64/asp116/glu152) commonly
referred to as a DD(35)E triad.6 The integration process consists
of several steps but the two viral enzyme catalyzed bond breaking
and forming events consisting of 30 processing of the respective vir-
al LTR ends in the cytoplasm and following nuclear entry strand
transfer whereby the recessed 30 hydroxyl groups of the viral
DNA ends nick host DNA resulting in a damaged DNA sequence
that is repaired by host cell mechanisms providing a permanently
lodged proviral DNA sequence.
OH O
N
N
H
N
F
N
Mg2+
SO2
Mg2+
X
N
OH
1 L-870,810
X
O
A
R
N
N
R
Y
HIV integrase is a 32 kDa, 288 amino acid protein that is be-
lieved to act in a multimeric state presumably as a tetramer to cat-
N
N
2
3
* Corresponding author. Tel.: +1 919 483 6006; fax: +1 919 483 6053.
E-mail address: brian.a.johns@gsk.com (B.A. Johns).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.090

B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1802–1806
1803
The seminal contributions from the laboratories of Merck and
N
O
OH N
N
OH
R
Shionogi resulting in the discovery of diketo-acid inhibitors and
their isosteric counterparts such as S-1360 served to establish a
unique pharmacophore consisting of a two-metal chelation motif
and a hydrophobic aromatic appendage requiring a fairly specific
spacing and orientation.7,8 The establishment of this specific phar-
macophore by the first generation of integrase inhibitors was key
to aiding in the design of more drug-like scaffolds. In particular
the early second generation work which evolved around the naph-
thyridine carboxamide scaffold represented by L-870,810 (1) and
related analogs gave us impetus to study this heterocyclic core in
an attempt to further understand the tolerance to alternative
chemical functionality.9 Our goal in this study was to investigate
whether a heterocyclic amide isostere as shown in 2 would achieve
the perceived co-planarity required for metal chelation and if so
would that arrangement have the appropriate coordinating ability
to bind the requisite magnesium ions (Fig. 1). Finally, would the
pendant non-metal binding substitution achieve the correct spatial
arrangement to provide potent enzymatic and antiviral activity? It
was rationalized that in order to achieve the necessary co-planarity
that the 5-membered ring heterocyclic amide isosteres repre-
sented by the oxazole, isoxazole, oxadiazole and triazole moieties
would be less sterically encumbered than their 6-membered ring
counterparts (e.g. pyridine or pyrimidine). The concerns with the
larger ring sizes are a propensity for the rings to adopt an orthog-
onal orientation thus prohibiting the system from achieving the
co-planar arrangement that was desired. We therefore set out to
explore a series of 5-membered ring heterocycles to determine
whether they would be viable amide isosteres at the 7-position
of the 8-hydroxy-1,6-naphthyridine scaffold.
a
H2N
N
CN
N
N
R
N
H
H
N
8
12
11
Scheme 2. Reagents and conditions: (a) Dioxane, AcOH,
l
w, 200 °C for 12a
(R = –CH2Ph, 55%), 12b (R = 4-F-C6H4CH2–, 16%), 12c (R = 4-Cl-C6H4CH2–, 37%),
12d (R = 3-Cl-C6H4CH2–, 5%), 12e (R = 3-OMe-C6H4CH2–, 21%), 12f (R = 3,4-di-OMe-
C6H3CH2–, 34%), 12g (R = PhCH2CH2–, 50%), 12h (R = 4-pyrCH2, 41%), 12i (R =
3-pyrCH2, 38%).
tion conditions involving heating with a hydrazide such as 11 would
result in the 1,3,4-oxadiazole ring system. Somewhat to our surprise,
heating this mixture in a microwave in the presence of acetic acid re-
sulted cleanly in conversion to the 1,2,4-triazole ring system (Scheme
2). While yields were modest under these conditions, the reaction ap-
peared to be robustly providing only the triazole ring system.
Since the above sequence was fortuitously providing the unex-
pected triazole series, we needed an alternative route to access the
symmetrical 1,3,4-oxadiazole series. Hydrolysis of the known
methyl ester 1311 led to acid 14 (Scheme 3). Alternatively, heating
ester 13 with hydrazine in ethanol provided the hydrazide interme-
diate 15. Coupling the above precursors with the appropriate aryl-
methyl hydrazide or phenylacetyl chloride provided a common
intermediate diacyl hydrazine which could be dehydrated upon
exposure to POCl3. It is evident from the above sequences that we
have chosen to not protect the reactive 8-hydroxyl group on the
naphthyridine core. Thisclearly resulted in decreased chemicalyield
and required a final hydrolysis typically to cleave acyl and phosphor-
ylated products present in the reaction mixture. Further optimiza-
tion of the synthetic chemistry is presented in a subsequentreport.12
As a final target to examine the pharmacophore effects of the
amide mimetics, we selected a set of N-methyl triazoles that would
help establish which heteroatom was key for metal chelation and also
might suggest if ring rotomers were relevant to this same binding.
To this end, nitrile 8 was treated with an 8:1 mixture of the N-
methyl acetylhydrazides 18 and 180 which were prepared as an
inseparable mixture from N-methyl hydrazide and 4-fluoropheny-
lacetyl chloride (Scheme 4). The condensation was sluggish but
We chose the 1,2,4-oxadiazole amide isostere due to synthetic
ease as our first target. To that end, the versatile intermediate 7-cy-
ano-8-hydroxy naphthyridine (8) was constructed from the alcohol
6
10 via a Mitsunobu coupling of tosylamide 5 followed by a Dieck-
mann-type cylization and elimination of toluenesulfinic acid
served to provide nitrile 8 (Scheme 1). Nitrile 8 was subsequently
treated with hydroxylamine to form the corresponding oxime
amine 9. Heating 9 with benzoyl chloride in pyridine led to acyla-
tion and dehydration to provide the desired unsymmetrical oxadi-
azole 10a along with its 8-O-benzoyl ester which was cleaved upon
treatment with basic methanol. The homologated benzyl analog
was in turn made by treatment of the oxime amine 9 in dioxane
with phenylacetyl chloride and subjecting the mixture to heating
in a microwave to provide oxadiazole 10b.
N
O
OH O
N
OH N
c -or- d
N
N
X
N
During the next iteration it was desired to make a series of oxadi-
azoleanalogs. Itwasinitiallyexpectedthatsubjectingnitrile8toreac-
17
11 R' = H
Y = -NH-NH2
16 R' = F
R'
13 X = OMe
14 X = OH
a
b
O
15 X = -NH-NH2
O
Y
O
R
Y = Cl
N
N
b
OiPr
OiPr
HN CN
R
+
Scheme 3. Reagents and conditions: (a) 13, LiOH, MeOH, reflux 18 h (87%); (b) 13,
NH2NH2, EtOH, reflux (70%); (c) for 17a (R0 = H) 14, 11, EDCI, HOBt, CH2Cl2; POCl3;
MeOH, K2CO3 (16%); (d) for17b (R0 = 4-F)15, 16, pyr., CH2Cl2; POCl3; MeOH, K2CO3 (8%).
7
4 R = H
CN
OH
a
N
6
TolSO 2
OH N
5 R = Ts-
O
N
NH2
N
OH
N
OH N
N
R
O
CN
N
N
c
e
N
N
N
18
N
N
a
19
8 R = CN
NH
10
8
NH
+
F
F
F
HN
18'
O
d
N
N
OH N
N
9 R =
NHOH
Scheme 1. Reagents and conditions: (a) TsCl, pyr, 0 °C, 30 min (94%); (b) DIAD,
PPh3, THF 0 °C to rt (71%); (c) NaOMe, MeOH, 0 °C to rt (89%); (d) hydroxylamine
HCl, K2CO3, EtOH, reflux (82%); (e) for 10a (R = Ph), BzCl, pyr, rt to 60 °C, then K2CO3,
F
20
MeOH (37%); for 10b (R = PhCH2–), PhCH2C(O)Cl, dioxane,
l
w, 190 °C (6%); for 10c
Scheme 4. Reagents and conditions: (a) AcOH, dioxane, l
w, 200 °C 19 (4%), 20 (24%).
(R = 4-F-C6H4CH2–), 4-F-C6H4CH2C(O)Cl, dioxane,
l
w, 160 °C (17%).

1804
B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1802–1806
after the addition of 4 equivalents of the hydrazide mixture two
products were isolated via preparative HPLC. Surprisingly, the mix-
ture favored the expected minor triazole 20 in a 3.4–1 ratio with
triazole 19 which arose from the major hydrazide 18 in the reac-
tion mixture. Perhaps the increased nucleophilicity of the second-
ary terminus of 180 reacted with nitrile 8 preferentially siphoning
Table 1
X
OH
A
N
R
N
Compound
A
R
IC50
(
l
M)a
EC50
n.d.
(l
M)b
T.I.c
n.d.
N O
10a
>100
0.95
R
R
N
N O
10b
1.9
55
N
N O
10c
12a
0.13
0.36
0.22
8.7
114
>4d
R
R
N
N N
F
F
N
H
N N
12b
12c
12d
12e
12f
0.13
0.64
1.03
2.8
.32
1.0
1.0
>35
>35
7
R
R
R
R
R
N
H
N N
1
N
H
N N
Cl
Cl
2
N
H
N N
OMe
n.d.
n.d.
N
H
N N
OMe
OMe
6.3
N
H
N N
12g
12h
2.4
4.6
>20
>35
n.d.
n.d.
R
R
N
H
N N
N
H
N
N N
N
12i
3.5
6.4
>3.6d
111
R
N
H
N N
17a
0.13
0.42
R
R
R
O
N N
O
17b
19
0.042
7.9
0.13
n.d.
>270
n.d.
F
F
N N
N
N N
N
O
20
21
>500
n.d.
n.d.
278
R
F
F
R
0.012
0.075
N
H
n.d. = not determined.
a
Recombinant HIV-1 integrase strand transfer assay.12
Pseudo-type HIV assay (PHIV).13
Therapeutic index (CC50/EC50).
b
c
d
Accurate determination of CC50 limited by solubility.

B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1802–1806
1805
off the minor hydrazide component. One cannot rule out a mixing
Cu
Cu
OH
of the hydrazides through a diacyl hydrazine intermediate as a re-
sult of the high temperatures experienced during the condensation
providing a pathway for increased amounts of 180 and the subse-
quent distortion of the ratio of products. The above result, how-
ever, was useful to our needs in that it provided sufficient
quantities of both isomers to examine for biological activity.
The inhibitory activity of the above heterocyclic amide replace-
ments were initially measured using a recombinant HIV-1 integr-
ase strand transfer assay.12 Where possible, these results were
followed up with an assessment of antiviral activity in a whole cell
pseudo-type HIV assay (PHIV).13 The 1,2,4-oxadiazole analog 10a
resulted in no measurable activity, however, when the benzylic
link was put in place in compound 10b activity in the micromolar
range was observed in the enzymatic assay along with measurable
antiviral effect in the PHIV assay. In comparison, the triazole con-
taining compounds showed similar potency against the enzyme
system for the benzyl and 4-fluorobenzyl substituted analogs 12a
and 12b, however, moving beyond the small halogens in the 4-po-
sition appeared to be detrimental to both enzyme and antiviral
activities (compounds 12d–12f) (see Table 1). In addition basic
nitrogens in the pyridylmethyl substituents (12h and 12i) also de-
creased activity as did the chain extended phenethyl group in ana-
log 12g. The corresponding 1,3,4-oxadiazole analogs showed the
most promising activity resulting in an improvement in both en-
zyme and antiviral activity when comparing the 4-fluoro deriva-
tive (17b) to the unsubstituted benzyl group (17a) consistent
with the triazole SAR. In addition, convincing therapeutic windows
were evident for both 1,3,4-oxadiazole analogs helping to validate
a robust antiviral effect. For comparison, the naphthyridine benzyl
amide 21 was examined in both assay systems and provided data
2- to 3-fold more potent than the corresponding oxadiazole 17b.
The methyl substituted triazole analogs 19 and 20 while not ex-
tremely potent do shed some light on the metal binding motif
present within these scaffolds. The lack of any measurable activity
in compound 20 is consistent with the methylated nitrogen remov-
ing an obligatory chelation group from coordination of the active
site magnesium. It also suggests the alternative rotomeric isomer
of these systems whereby the single lone nitrogen in position 4
of the triazole in 20 would coordinate the metals is not operable.
Meanwhile compound 19 while less potent than the non-methyl-
ated example 12b does retain some activity suggesting metal
coordination.
O
N
NH2
N
O
N
CN
N
N
CN
N
b
c
N
OH
N
N
H
N
24
SO2
R
SO2
SO2
8 R = H
22 R = Br
25
a
e
23
N
OH N
N
O
OH
N
N
N
d
N
N
H
N
N
N
F
SO2
F
SO2
27
26
Scheme 5. Reagents and conditions: (a) NBS, CHCl3(90%); (b) 23, Cu2O, pyr, 105 °C
(73%); (c) NH2OH HCl, K2CO3, EtOH reflux (65%); (d) 4-F-C6H4CH2C(O)Cl, dioxane,
l
w, 160 °C, then EDTA (aq) (11%); (e) 4-F-C6H4CH2C(O)NHNH2, Dioxane, AcOH,
lw,
200 °C (23%).
32. This material was found to undergo smooth dehydration to give
the desired oxadiazole upon treatment with modified Mitsunobu
conditions. Other methods including using the Burgess Reagent or
POCl3 also gave product but were not as preferable in our hands as
the PPh3/I2 conditions. Finally, the 8-hydroxyl group was freed up
using the in situ generated TMSI conditions of Jung to provide the
1,3,4-oxadiazole 33.14 (Scheme 6).
With the three sultam containing analogs in hand we were able
to evaluate the effects of the 5-substition on activity versus the 5-
protio analogs for each as well as again compare the triazole and
oxadiazoles to one another with similar analogs (Table 2). Interest-
ingly, the 1,2,4-oxadiazole analog 26 was completely inactive in
our hands. This was surprising to us and not consistent with our
expectations nor is it explained by solubility or permeability prop-
erties. A modest improvement in potency was observed for triazole
27 compared to protio derivative 12b. However, more noteworthy
is the improved therapeutic index observed in the C5-substituted
analog (>104-fold for 27 vs 7-fold for 12b). A significant improve-
ment of antiviral potency was also observed for the 1,3,4-oxadiaz-
ole analog 33 compared to its 5-protio counterpart 17b. This low
nM potency is now approaching that of L-870,810 (1) which has
shown clinical efficacy.
Now that we had established that the 5-membered heterocycles
were viable metal chelation components in conjunction with the 8-
hydroxynaphthyridine scaffold, we desired to examine further
structural effects on activity levels. The C5 position appeared to be
the most amenable for further functionalization and since the sul-
tam group in L-870,810 appeared to have beneficial effects on the
amide series of compounds we chose this as our first group to ex-
plore.9 To that end, nitrile 8 was brominated followed by a copper
mediated coupling of sultam 2311 resulting in the desired adduct
24, however, the material was isolated as a fairly insoluble copper
complex. Nonetheless this intermediate served useful as it could
be taken on as the complex and treated with hydroxylamine and
subsequently condensed with 4-fluorophenyacetyl chloride or con-
densed directly with 4-fluorophenylacetic hydrazide to provide the
1,2,4-oxadiazole 26 or 1,2,4-triazole 27, respectively (Scheme 5).
Similarly, we also wanted to look at the 1,3,4-oxadiazole isomer.
This material was made starting with known 5-bromo ester 28.11
Since the phenol hydroxyl group has been problematic throughout
several of the previous syntheses we decided to block that position
as the corresponding methyl ether 29. The protected hydroxyl group
not surprisingly behaved much better in the subsequent sultam cou-
pling to give ester 30 which was hydrolyzed and coupled to 4-fluor-
ophenylacetic hydrazide to provide the diacyl hydrazine derivative
OR
O
CO2Me
N
CO2R
N
b
d
N
N
Br
N
SO2
28 R = H
29 R = Me
a
30 R = Me
31 R = H
Na+
c
N
O
O
N
O
N
O
e,f,g
N
N
NH
HN
O
N
N
33
N
F
SO2
SO2
32
F
Scheme 6. Reagents and conditions: (a) MeI, Cs2CO3, DMF (76%); (b) 23, Cu2O, 2,20-
dipyridyl, DMF 125 °C, then EDTA (61%); (c) LiOH (aq), THF/MeOH (99%); (d)
F-C6H4CH2C(O)NHNH2, EDCI, HOBt, CH2Cl2 (90%); (e) PPh3, I2, Et3N, CH2Cl2 (56%); (f)
TMSCl, NaI, MeCN (93%); (g) NaOH, MeOH (52%).

1806
B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1802–1806
Table 2
References and notes
Comparison of C5-sultam substituted analogs
1. Walensky, R. P.; Paltiel, A. D.; Losina, E.; Mercincavage, L. M.; Schackman, B. R.;
Sax, P. E.; Weinstein, M. C.; Freedberg, K. A. J. Infect. Dis. 2006, 194, 11.
2. De Clercq, E. Nat. Rev. Drug Discov. 2007, 6, 1001.
X
OH
A
N
3. Crescenzi, B.; Gardeli, C.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore,
G.; Petrocchi, A.; Poma, M.; Rowley, M.; Scarpelli, R.; Summa, V. WO 03/
035077, 2003 Chem. Abstr. 2003, 138, 354001.
4. Markowitz, M.; Morales-Ramirez, J. O.; Nguyen, B. Y.; Kovacs, C. M.; Steigbigel,
R. T.; Cooper, D. A.; Liporace, R.; Schwartz, R.; Isaacs, R.; Gilde, L. R.; Wenning,
L.; Zhao, J.; Teppler, H. J Acquir. Immune Defic. Syndr. 2006, 43, 509.
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Wolfe, A.; Egbertson, M.; Bourgeois, M.; Melamed, J.; Wai, J. S.; Young, S.; Vacca,
J.; Hazuda, D. J. Proc. Natl. Acad. Sci. USA 2002, 99, 6661; (b) Hazuda, D. J.; Young,
S. D. Adv. Antiviral Drug Des. 2004, 4, 63.
N
F
N
SO2
Compound
A
IC50
(
l
M)a
EC50
n.d.
(l
M)b
T.I.c
n.d.
N O
26
>100
R
N
7. Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.; Embrey, M. W.; Tran, L. O.;
Melamed, J. Y.; Langford, H. M.; Guare, J. P., Jr.; Zhuang, L.; Grey, V. E.; Vacca, J.
P.; Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.;
Stillmock, K. A.; Schleif, W. A.; Gabryelski, L. J.; Young, S. D. J. Med. Chem. 2000,
43, 4923.
N N
27
33
1
0.011
0.002
0.013
0.24
>104
198
R
R
N
H
8. (a) Fujishita, T.; Yoshinaga, T. WO 99/50245 Chem. Abstr. 1999, 131, 271806; (b)
Fujishita, T.; Yoshinaga, T.; Sato, A. WO 00/039086 Chem. Abstr. 2000, 133, 89529.
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Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.;
Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M.
D.; Espeseth, A. S.; Jin, L.; Chen, I. -W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong,
B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.;
Holloway, M. K.; Young, S. D. Proc. Natl. Acad. Sci. USA 2004, 101, 11233; (b)
Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson, M. S.; Payne, L. S.;
Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K.
A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Leonard, Y. M.;
Lynch, J. J.; Michelson, S. R.; Young, S. D. J. Med. Chem. 2003, 46, 453.
10. Ornstein, P. L.; Schaus, J. M.; Chambers, J. W.; Huser, D. L.; Leander, J. D.; Wong,
D. T.; Paschal, J. W.; Jones, N. D.; Deeter, J. B. J. Med. Chem. 1989, 32, 827.
11. Anthony, N. J.; Gomez, R. P.; Bennett, J. J.; Young, S. D.; Egbertson, M.; Wai, J. S.
WO 02/30426 Chem. Abstr. 2002, 136, 325438.
N N
O
0.013
0.002
O
R
1795
N
H
n.d. = not determined.
Recombinant HIV-1 integrase strand transfer assay.12
Pseudo-type HIV assay (PHIV).13
Therapeutic index (CC50/EC50).
a
b
c
In summary, the work presented in this communication has
12. Boros, E. E.; Johns, B. A.; Garvey, E. P.; Koble, C. S.; Miller, W. H. Bioorg. Mad.
Chem. Lett. 2006, 16, 5668.
served to establish the oxadiazole and triazole heterocycles as via-
ble components of the chelation motif involved in the 8-hydrox-
ynaphthyridine integrase scaffold. Furthermore, a preliminary
examination of C5 substitution showed significant improvements
in antiviral activity on par with that of the validated clinical candi-
date L-870,810. Further SAR optimization of these heterocycle
substituted 8-hydroxy-naphthyridine integrase inhibitors is pre-
sented in due course.15
13. Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster, S. A.; Miller, W. H.; Ferris, R. G.;
Hazen, R. J.; Underwood, M. R.; Boros, E. E.; Thompson, J. B.; Weatherhead, J. G.;
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M.; Wakasa-Morimoto, C.; Miki, S.; Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T.
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Lyster, M. A. J. Org. Chem. 1977, 42, 3761.
15. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.;
Foster, S. A.; Jeffrey, J. L.; Miller, W. H. Bioorg. Med. Chem. Lett. 2009, 19, 1807.