Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

Article abstract of DOI:10.1021/jm034082o

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

Full text of DOI:10.1021/jm034082o

4236
J . Med. Chem. 2003, 46, 4236-4239
inhibitors of HIV replication without mechanistic bias
was implemented. The indole derivative 1, a member
of a purely prospective library of amides prepared
largely from commercially available components, emerged
from that exercise as a mechanistically novel and
effective inhibitor of HIV that was devoid of overt
cytotoxicity. It was quickly established that 1 was an
inhibitor of a range of HIV-1 isolates and that the
activity was independent of the coreceptor used by these
viruses to enter host cells, data summarized in Table
1. The selectivity index based on the cytotoxicity as-
sociated with 1 in MT-2 and PM1 cells ranged from 28
(NL4-3) to 1686 (LAI). Moreover, at a concentration of
200 µM, indole 1 was without significant inhibitory
activity toward a panel of viruses composed of HIV-2,
simian immunodeficiency virus (SIV), murine leukemia
virus (MuLV), respiratory syncytial virus (RSV), human
cytomegalovirus (HCMV), bovine viral diarrhea virus
(BVDV), vesicular stomatitis virus (VSV), and influenza
virus. The cytotoxicity of 1 toward the panel of unin-
fected host cell types used to grow these viruses was
minimal, with 50% inhibitory levels (CC50) ranging from
99 to greater than 200 µM. Cytotoxicity was most
evident in Hep-2 cells, a human larynx carcinoma cell
line that is a particularly sensitive sentinel. A series of
mechanistic studies deduced that 1 compromised the
interaction of the viral surface protein gp120 with the
host cell receptor CD4, providing the first example of a
small molecule with a mode of action that has hitherto
proven elusive.5 As a mechanistically unique HIV-1
inhibitor with druglike qualities,6,7 1 offered a compel-
ling point of departure, and in this communication
optimization into the prototype BMS-378806 (3) is
described.
Discover y of 4-Ben zoyl-1-[(4-m eth oxy-1H-
p yr r olo[2,3-b]p yr id in -3-yl)oxoa cetyl]-2-
(R)-m eth ylp ip er a zin e (BMS-378806): A
Novel HIV-1 Atta ch m en t In h ibitor Th a t
In ter fer es w ith CD4-gp 120 In ter a ction s†
Tao Wang,*,‡ Zhongxing Zhang,‡ Owen B. Wallace,‡
Milind Deshpande,§ Haiquan Fang,‡ Zheng Yang,
Lisa M. Zadjura, Donald L. Tweedie,
Stella Huang,X Fang Zhao,2 Sunanda Ranadive,2
Brett S. Robinson,| Yi-Fei Gong,| Keith Ricarrdi,|
Timothy P. Spicer,| Carol Deminie,| Ronald Rose,|
Hwei-Gene Heidi Wang,| Wade S. Blair,|
Pei-Yong Shi,| Pin-fang Lin,| Richard J . Colonno,| and
Nicholas A. Meanwell*,‡
Department of Discovery Chemistry,
Department of Lead Discovery, Department of Virology,
Department of Analytical Sciences, Department of
Metabolism and Pharmacokinetics, The Bristol-Myers
Squibb Pharmaceutical Research Institute,
Wallingford, Connecticut 06492 and Department of
Pharmaceutics, The Bristol-Myers Squibb Pharmaceutical
Research Institute, New Brunswick, New J ersey 08903
Received April 18, 2003
Abstr a ct: Indole derivative 1 interferes with the interaction
of the HIV surface protein gp120 with the host cell receptor
CD4. The 4-fluoro derivative 2 exhibited markedly enhanced
potency and was bioavailable in the rat, dog, and cynomolgus
monkey when administered orally as a solution formulation.
However, aqueous suspensions of 2 were poorly bioavailable,
indicative of dissolution-limited absorption. The 7-azaindole
derivative 3, BMS-378806, exhibited improved pharmaceutical
properties while retaining the HIV-1 inhibitory profile of 2.
In tr od u ction . The advent of highly active anti-
retroviral therapy (HAART), a combination cocktail of
inhibitors of HIV reverse transcriptase and protease,
has provided an effective means of controlling viral load
and disease progression in HIV-infected individuals.1
However, compliance with drug dosing regimens can be
challenging because of the severity of side effects and a
significant pill burden, factors that have prompted
examination of the concept of scheduled treatment
interruptions (STI).2 These limitations have contributed
to the development and dissemination of resistant
viruses, an emerging and significant problem that
portends a need for new anti-retroviral agents that
interfere with different targets in the replication cycle,
are better tolerated and offer more convenient dosing
schedules.3,4 As the preliminary step toward that objec-
tive, a cell-based screening assay designed to capture
The initial survey of structure-activity studies as-
sociated with indole 1 revealed that potency was ex-
quisitely sensitive to substitution at C-4 of the hetero-
cycle and the fluoro derivative 2 very quickly emerged
as a molecule with a profile of considerable interest as
a potential candidate for development. The inhibitory
activity of 2 toward the panel of macrophage- and T cell-
tropic HIV-1 strains is compared with 1 in Table 1.
These viruses are laboratory strains that use either
CCR5 (M-tropic) or CXR4 (T-tropic) coreceptors to enter
cells and are classified as B subtypes. The fluoro
analogue 2 is consistently more potent than the proto-
type 1, with an advantage ranging from 10- to 1585-
fold, dependent upon virus identity. In the presence of
40% human serum, the EC50 values increased by 2-3-
fold, reflecting modest protein binding that was subse-
quently determined by ultrafiltration to be 93% in
human plasma. The profile of 2 in a series of in vitro
assays designed to evaluate pharmacokinetic properties
indicated good intestinal membrane permeability (Ca-
co-2 permeability of 100 nm/s) and an intermediate
clearance in man based on the stability of the compound
in human liver microsomes. However, 2 was less stable
in rat liver microsomes (RLM), a result that predicted
high clearance in this species, and subsequently con-
firmed in vivo (vide infra). Of the human metabolizing
enzymes, only CYP2C19 was significantly affected by
* Author for correspondence: Nicholas A. Meanwell, Department
303, The Bristol-Myers Squibb Pharmaceutical Research Institute,
5
Research
Parkway,
Wallingford,
CT
06492.
e-mail:
Nicholas.Meanwell@bms.com; Tel. (203)-677-6679; FAX: (203)-677-
7702.
† Dedicated to the memory of Dr. Steven M. Seiler: scientist,
collaborator, and friend.
‡ Department of Discovery Chemistry.
§ Department of Lead Discovery.
| Department of Virology.
X Department of Analytical Sciences.
Department of Metabolism and Pharmacokinetics.
2 Department of Pharmaceutics.
10.1021/jm034082o CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/30/2003

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 20 4237
Ta ble 1. HIV-1 Inhibitory Activity and Cytotoxicity Associated with Compounds 1-3a
1
2
3 (BMS-378806)
virus
LAI (T)
SF-2 (T)
NL4-3 (T)
Bal (M)
SF-162 (M)
J RFL (M)
TLAV (dual)
EC50 (nM)
86 ( 24
1030 ( 29
5130 ( 2620
28 700 ( 4200
230 ( 140
ND
CC50 (µM)
EC50 (nM)
CC50 (µM)
EC50 (nM)
CC50 (µM)
145 ( 23 In MT-2 cells
2.93 ( 1.41
62.4 ( 33.7
30.8 ( 18.6
18.1 ( 8.4
ND
2.39 ( 0.85
13.6 ( 7.8
146 ( 74 in MT-2 cells
2.68 ( 1.64
26.5 ( 3.5
2.94 ( 2.01
15.5 ( 6.8
3.46 ( 0.81
1.47 ( 0.63
0.85 ( 0.13
>300 in MT-2 cells
>200 in PM1 cells
52.5 ( 1.2
>300 in PM1 cells
>300 in MT-2 cells
149 ( 65
145 ( 23 in MT-2 cells
146 ( 74 in MT-2 cells
a
ND: Not determined. T ) T-tropic virus that utilizes the CXCR-4 coreceptor; M ) macrophage-tropic virus that utilizes the CCR5
coreceptor; dual ) virus utilizing both CXCR4 and CCR5 coreceptors for entry.
Ta ble 2. Pharmacokinetic Parameters for Compounds 2 and 3a
from 5 to 25 mpk. In the dog, oral bioavailability was
>100% at a dose of 10 mpk when compared to a 2 mpk
dose administered intraveneously. However, a marked
reduction in exposure was encountered when dosing
suspensions of 2 in 0.75% (w/w) Methocel A4M and 0.5%
(w/w) Pluronic F68. In the rat, a dose of 5 mpk of 2
administered as a mean particle size of 46 µm resulted
in no detectable oral exposure. Examination of material
prepared as a nanosuspension in 1% (w/w) Pluronic
F108 provided only a marginal improvement, with
bioavailability determined to be 4% in the rat and 36%
in the dog at a dose of 1 mpk. These results are
indicative of problems associated with drug dissolution,
a phenomenon reflected in the solubility profile of 2,
which was determined to be 5 µg/mL in water, 100 µg/
mL in a mixture of 5% Tween 80 in water and 4.6 mg/
mL in PEG 400, and related to the high melting point,
236 °C.
2
3
Rat
iv/po dose (mg/kg)
5/5
9.4
0.15
48
0.99
1/5
19
F
po (%)
C
max,po (µM)
0.22
32
0.56
CLtot (mL/min/kg)
Vss (L/kg)
Dog
These findings prompted a search for a compound
with a similar antiviral profile to 2 but with improved
pharmaceutical properties, an objective fulfilled with the
preparation of the azaindole derivative 3, recognized as
BMS-378806. The introduction of a nitrogen atom into
the heterocycle and installation of a more polar and
electron-donating methoxy substituent8,9 at C-4 pro-
vided a compound with aqueous solubility from the
crystalline form of 170 µg/mL, a 34-fold improvement
compared to 2. The solubility of 3 improves to 1.3 mg/
mL at pH ) 2.1 and 3.3 mg/mL at pH ) 11, a solubility
profile that reveals the amphoteric nature of the com-
pound and estimates the pKa of the protonated form as
2.9 while that of the free base is approximately 9.6.
The antiviral effects of the azaindole 3 are presented
in Table 1 where it is readily apparent that all of the
activity of indole 2 against the panel of B subtype HIV-1
strains is fully preserved. In MT-2 cells infected with
HIV-1 LAI virus, the presence of 40% human serum
increased the EC50 value by a modest 1.2-fold while the
addition of 1 mg/mL of R1 acid glycoprotein was without
effect. Consistent with this result, plasma protein
binding, determined using an ultrafiltration method at
a plasma concentration of 1 µg/mL, was found to be 73,
63, 44, and 54% in human, rat, dog and monkey plasma,
respectively.
iv/po dose (mg/kg)
2/10
∼100
18
2.4
1.8
0.67/3.4
77
7.4
5.2
0.47
F
po (%)
C
max,po (µM)
CLtot (mL/min/kg)
Vss (L/kg)
Monkey
2/10
iv/po dose (mg/kg)
0.67/3.4
24
0.51
10
F
po (%)
∼100
C
max,po (µM)
34
CLtot (mL/min/kg)
3.1
0.24
Vss (L/kg)
0.39
a
Administered as a solution in poly(ethylene glycol) 400/ethanol
(90:10 v/v).
2, IC50 ) 7 µM, with half-maximal inhibition of the other
major isoforms >10 µM. These data, when combined
with the observation that 2 is metabolized by multiple
P450 isoforms, anticipate minimal drug-drug interac-
tions, of particular importance in the arena of HIV
therapy where drug combinations are the standard of
care.
The pharmacokinetic properties of 2, administered as
a solution in poly(ethylene glycol) 400 (PEG 400) and
ethanol (90:10 v/v), in the rat, dog and cynomolgus
monkey are summarized in Table 2. Oral bioavailability
was excellent in the dog and monkey, but poor in the
rat, where the high clearance was anticipated based on
the poor stability in RLM. The maximum plasma
concentrations achieved in all three species were well
in excess of the antiviral EC50 values determined in the
cell culture assays. However, while exposure in the rat
and dog was responsive to dose escalation, nonlinear
pharmacokinetic properties were observed in these
species. In rats, the bioavailability increased 2-fold and
Cmax increased 10-fold when the dose was increased
In a series of biochemical assays, 3 was not an
effective inhibitor of HIV integrase, protease, or reverse
transcriptase, but did compete with soluble CD4 binding
to a monomeric form of gp120 in an ELISA assay with
IC50 ) ∼100 nM. The generation and sequencing of
resistant viruses identified M426L, M434I/V and M475I
of gp120 as primary resistance mutations in the HIV-1
strains NL4-3 and LAI. Recombinant viruses contain-

4238 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 20
Letters
Sch em e 1a
a
(a) 1. ClCOCO2Me/AlCl3/CH2Cl2 (79%); 2. K2CO3/MeOH/H2O (90%); (b) DEPBT/Pr2EtN/DMF (81%); (c) mCPBA/acetone (91%); (d)
HNO3/CF3CO2H; (e) 1. MeONa/MeOH/∆; 2. PCl3/EtOAc (50% over three steps).
Sch em e 2
ing these individual substitutions display a resistant
phenotype. The M426L and M475I mutations map to
the pocket on gp120 that interacts with phenylalanine
43 of CD4, a residue that has been shown to be critical
to recognition and which provides additional support for
the proposed mode of action.10 The specificity of 3
toward inhibition of HIV-1 was confirmed by evaluation
against HIV-2, SIV, MuLV, RSV, HCMV, BVDV, VSV,
and influenza virus, with no significant inhibitory
activity observed at concentrations ranging from 10 to
30 µM and no overt cytotoxicity toward the host cells,
CC50 values > 225 µM.
potential for cardiac problems was confirmed in a rabbit
purkinje fiber assay, where no significant changes in
action potential duration were seen at 30 µM, and in
the dog, where no ECG abnormalities where were
observed following doses as high as 200 mg/kg. In
toxicology studies, 3 was well tolerated in rats at doses
of 100 mg/kg/day for 2 weeks and in dogs at doses of 90
mg/kg for 10 days.
The pharmacokinetic properties of 3 in the rat, dog,
and cynomolgus monkey are summarized in Table 2.
The oral bioavailability of 3 in rats, administered as a
solution in PEG 400/EtOH (90:10 v/v), was 19% at a
dose of 5 mg/kg while an aqueous crystalline suspension
of free base in 0.75% (w/w) Methocel A4M Premium
administered orally at the same dose afforded a relative
bioavailability of 61%. Importantly, dose-proportional
increases in the AUC and Cmax were observed between
doses of 5 and 25 mpk, when 3 was administered either
in the solution or suspension formulation. In all three
species, plasma levels of drug exceeded the concentra-
tions required to half-maximally inhibit virus replication
in vitro. The volume of distribution of 3 ranged from
0.4 to 0.6 L/kg, indicative of partitioning beyond plasma;
however, examination of brain levels in the rat revealed
minimal CNS penetration.
Additional preclinical studies revealed that 3 is not
a potent inhibitor of any of the five major human CYP
isoforms, evaluated as recombinant preparations, with
IC50 values of >100 µM for CYP1A2 and CYP2C9, 23
µM for CYP2C19, 20 µM for CYP2D6, and 39 to 81 µM
for CYP3A4. Moreover, since 3 is metabolized by
CYP450 1A2, 2D6, and 3A4, it is unlikely to lead to
severe drug-drug interactions in a clinical setting.
Safety profiling of 3 provided no evidence of mutage-
nicity in an Ames reverse mutation assay at 1600 µg/
plate and only weak inhibition of a cloned HERG
channel (10.9% inhibition at 10 µM). The limited
Ch em istr y. The synthesis of BMS-378806 (3) is
depicted in Scheme 1 and is initiated by acylating
7-azaindole (4) with methyl chlorooxoacetate in the
presence of AlCl3.11,12 Hydrolysis of the resulting ester,
using K2CO3 in aqueous MeOH, was followed by cou-
pling with the benzoylated piperazine 6, a reaction
mediated by 3-(diethoxyphosphoryloxy)-1,2,3-benzotri-
azin-4(3H)-one13 in the presence of N,N-diisopropyleth-
lyamine (iPr2NEt, Hunig’s base) in DMF, to afford 7 in
an overall yield of 57%. The piperazine 6 was, in turn,
obtained by exposing (R)-(-)-2-methylpiperazine and
methyl benzoate to 1 mol equiv of diethylaluminum
chloride in CH2Cl2, a reaction proceeding with excellent
regiospecificity, as summarized in Scheme 2.14 Incor-
poration of the methoxy substituent at the 4-position
of 7 was accomplished by a serial process, initiated by
oxidation of the nitrogen atom of the heterocycle15 and
followed by nitration with fuming HNO3 in CF3CO2H,
which afforded the 4-nitro N-oxide 9.16 Heating 9 with
an excess of NaOMe in MeOH resulted an ipso displace-
ment of nitrite,17 setting the stage for the final trans-
formation to 3. This was accomplished in a straightfor-
ward fashion by reduction of the N-oxide using PCl3 in
EtOAc.17 The yield of 3 from the unsubstituted N-oxide
8 was 50% for the three steps, with an overall yield of
26% from 4. That nitration of N-oxide 8 had occurred

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 20 4239
at C-4 was established by analysis of a H-15N HMBC
2D NMR experiment in which the N-7 atom of 3,
resonating at δ183 ppm showed a strong cross-peak with
the C-6 proton resonating at δ 8.23, while the parameter
of the experiment was optimized for a 8 Hz coupling
constant. Literature precedent indicates that 2J (HN)
for pyridine and quinoline derivatives is approximately
11 Hz, falling off to less than 0.3 Hz for coupling across
four bonds.18 The strength of the cross coupling in the
1H-15N HMBC 2D NMR experiment is consistent with
the methoxy substituent located at C-4 rather than C-2,
regiochemistry subsequently confirmed by single-crystal
X-ray analysis.19 The C-2 proton of 3 resonated as two
singlets at δ 8.09 and 8.15 that coalesced to a single
singlet when the DMSO-d6 solution was warmed to 120
°C, indicating that 3 exists as a pair of rotational
conformers at room temperature.
1
gp120 to the CD4 receptor. Bioorg. Med. Chem. Lett. 1993, 3,
2851-2856. (c) Chen, S.; Chrusciel, R. A.; Nakanishi, H.;
Raktabutr, A.; J ohnson, M. E.; Sato, A.; Weiner, D.; Hoxie, J .;
Uri Saragovi, H.; Greene, M. I.; Kahn, M. Design and synthesis
of a CD4 â-turn mimetic that inhibits human immunodeficiency
virus envelope glycoprotein gp120 binding and infection of
human lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 1992, 89,
5872-5876. (d) Zhang, J . L.; Choe, H.; Dezube, B. J .; Farzan,
M.; Sharma, P. L.; Zhou, X. C.; Chen, L. B.; Ono, M.; Gillies, S.;
Wu, Y.; Sodroski, J . G.; Crumpacker, C. S. The bis-azo compound
FP-21399 inhibits HIV-1 replication by preventing viral entry.
Virology 1998, 244, 530-541.
(6) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J .
Experimental and computational approaches to estimate solubil-
ity and permeability in drug discovery and development settings.
Adv. Drug Deliv. Rev. 1997, 23, 3-25.
(7) Snyder, D. W.; Bach, N. J .; Dillard, R. D.; Draheim, S. E.;
Carlson, D. G.; Fox, N.; Roehm, N. W.; Armstrong, C. T.; Chang,
C. H.; Hartley, L. W.; J ohnson, L. M.; Roman, C. R.; Smith, A.
C.; Song, M.; Fleisch, J . H. Pharmacology of LY315920/S-5920
[[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-
acetate,
a potent and selective secretory phospholipase A2
inhibitor: A new class of anti-inflammatory drugs, SPI. J .
Pharmacol. Exp. Ther. 1999, 288, 1117-1124.
The preparation of 2 was accomplished from 4-fluor-
oindole using a synthetic protocol similar to that used
to secure 7 but more convenient, taking advantage of
the enhanced reactivity of 4-fluoroindole toward oxalyl
chloride in Et2O, which allowed the corresponding acid
chloride to be realized in a single procedure. Exposure
of this acid chloride to N-benzoylpiperazine in the
(8) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.;
Lien, E. J . “Aromatic” substituent constants for structure-
activity correlations. J . Med. Chem. 1973, 16, 1207-1216.
(9) In addition to modifications of the indole moiety of 2, the
azaindole
3 incorporates a 2-(R)-methyl substituent in the
piperazine ring. The introduction of this methyl group can affect
potency and both physical and pharmacokinetic properties.
However, the role of 2-(R)-methyl moiety in modulating potency
has been found to be somewhat enigmatic, being dependent upon
the context and optimally able to provide an advantage of up to
1 order of magnitude. In the example at hand, the 2-(R)-methyl
group in 3 exerts a minimal effect on potency but exerts a
favorable effect on aqueous solubility.
i
presence of Pr2NEt in THF afforded 2.
In summary, optimization of a structurally elemen-
tary and effective inhibitor of HIV attachment (1) into
a compound (3) with improved antiviral potency, at-
tractive pharmaceutical and pharmacokinetic proper-
ties, and a safety profile appropriate for more advanced
studies has been accomplished. These indole-based
compounds represent the basic pharmacophore of a new
class of HIV-1 inhibitor that are the first small mol-
ecules able to effectively and potently interfere with the
interaction of the HIV surface protein gp120 and the
primary host cell receptor CD4, the initial step of HIV
entry. As such, they add to the emerging repertoire of
HIV-1 inhibiting compounds that interfere with the
viral entry process, providing an effective complement
to the CCR5 and CXR4 coreceptor antagonists and
enfuvirtide, the gp41 fusion inhibitor. A more detailed
analysis of the profile of 3 as an inhibitor of HIV-1
clinical isolates will be presented in due course.21
(10) Kwong, P. D.; Wyatt, R.; Robinson, J .; Sweet, R. W.; Sodroski,
J .; Hendrickson, W. A. Structure of an HIV gp120 envelope
glycoprotein in complex with the CD4 receptor and a neutral-
izing human antibody. Nature 1998, 393, 648-659.
(11) (a) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J .; Meanwell, N. A.;
Kadow, J . F.; Wang, T. An effective procedure for the acylation
of azaindoles at C-3. J . Org. Chem. 2002, 67, 6226-6227. (b)
Yeung, K.-S.; Farkas, M. E.; Qiu, Z.; Yang, Z. Friedel-Crafts
acylation of indoles in acidic imidazolium chloroaluminate ionic
liquid at room temperature. Tetrahedron Lett. 2002, 43, 5793-
5795.
(12) An alternative approach relied upon the reaction of the zinc salt
of 4, generated by treatment with MeMgI and subsequent
exchange with ZnCl2, in CH2Cl2 with methyl chlorooxoacetate.
(13) Li, H.; J iang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Good, M.
3-(Diet h oxyph osph or yloxy)-1,2,3-ben zot r ia zin -4(3H )-on e
(DEPBT): A new coupling reagent with remarkable resistance
to racemization. Org. Lett. 1999, 1, 91-93.
(14) Wang, T.; Zhang, Z.; Meanwell, N. A. A one-pot procedure for
the regioselective preparation of mono-benzoylated derivatives
of unsymmetrical piperazines. J . Org. Chem. 2000, 65, 4740-
4742.
(15) Harada, N.; Kawaguchi, T.; Inoue, I.; Ohashi, M.; Oda, K.;
Hashiyama, T.; Tsujihara, K. Synthesis and antitumor activity
of quaternary salts of 2-(2′-oxoalkoxy)-9-hydroxyellipticines.
Chem. Pharm. Bull. 1997, 45, 134-137.
(16) Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.; Crifantini,
M.; Martelli, S. Synthesis of 4-amino-1-â-D-ribofuranosyl-1H-
pyrrolo[2,3-b]pyridine (1-Deazatubercidin) as a potential anti-
tumor agent. J . Med. Chem. 1982, 25, 1258-1261.
(17) Fanghaenel, E.; Hucke, A.; Lochter, T. H.; Baumeister, U.;
Hartungm, H. Ring transformation of 1,1-dioxo-1,3-thiazine-6-
carbaldehydes with nitrogen nucleophiles to substituted pyri-
dine-3-sulfonanilides. Synthesis 1996, 1375-1379.
(18) Levy, G. C.; Lichter, R. L. Nitrogen-15 Nuclear Magnetic
Resonance Spectroscopy; Wiley-Interscience: New York, 1979;
Chapter 4, pp 115 and 117.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data for the preparation of compounds 2,
3, and 5-9. This material is available free of charge via the
Internet at http://pubs.acs.org.
Refer en ces
(1) Richman, D. D. HIV chemotherapy. Nature 2001, 410, 995-
1001.
(2) Gulick, R. M. Structured treatment interruption in patients
infected with HIV. A new approach to therapy? Drugs 2002, 62,
245-253.
(3) Little, S. J .; Holte, S.; Routy, J .-P.; Daar, E. S.; Markowitz, M.;
Collier, A. C.; Koup, R. A.; Mellors, J . W.; Connick, E.; Conway,
B.; Kilby, M.; Wang, L.; Whitcomb, J . M.; Hellmann, N. S.;
Richman, D. S. Antiretroviral-drug resistance among patients
recently infected with HIV. New Engl. J . Med. 2002, 347, 385-
394.
(4) Miller, M. D.; Hazuda, D. J . New antiretroviral agents: Looking
beyond protease and reverse transcriptase. Curr. Opin. Micro-
biol. 2001, 4, 535-539.
(5) (a) Finberg, R. W.; Diamond, D. C.; Mitchell, D. B.; Rosenstein,
Y.; Soman, G.; Norman, T. C.; Schreiber, S. L.; Burakoff, S. J .
Prevention of HIV-1 infection and preservation of CD4 function
by the binding of CPFs to gp120. Science 1990, 287, 287-291.
(b) J arvest, R. L.; Breen, A. L.; Edge, C. M.; Chaikin, M. A.;
J ennings, L. J .; Truneh, A.; Sweet, R. W.; Hertzberg, R. P.
Structure-directed discovery of an inhibitor of the binding of HIV
(19) Qi Gao, unpublished results.
(20) (a) Blair, W. S.; Lin, P.-f.; Meanwell, N. A.; Wallace, O. B. HIV-1
entry - an expanding portal for drug discovery. Drug Discovery
Today 2000, 5, 183-194. (b) O’Hara, B. M.; Olson, W. C. HIV
entry inhibitors in clinical development. Curr. Opin. Pharmacol.
2002, 2, 523-528.
(21) Lin, P.-f. M.; Blair, W. S.; Wang, T.; Spicer, T. P.; Guo, Q.; Zhou,
N.; Gong, Y.-F.; Wang, H.-G.; Rose, R.; Yamanaka, G. A.;
Robinson, B. S.; Li, C.-B.; Kimel, B. J .; Fang, H.; Demers, G.;
Deminie, C.; Fridell, R. A.; Yang, Z.; Zadjura, L. M.; Meanwell,
N. A.; Colonno, R. J . A small molecule HIV-1 inhibitor that
targets the HIV-1 envelope and inhibits CD4 receptor binding.
Proc. Natl. Acad. Sci. U.S.A., in press.
J M034082O