Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: The discovery of GW0385

Article abstract of DOI:10.1016/j.bmcl.2006.01.035

A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.

Full text of DOI:10.1016/j.bmcl.2006.01.035

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1788–1794
Ultra-potent P1 modified arylsulfonamide HIV protease
inhibitors: The discovery of GW0385
John F. Miller,a,* C. Webster Andrews,a Michael Brieger,a Eric S. Furfine,a
Michael R. Hale,b Mary H. Hanlon,a Richard J. Hazen,a Istvan Kaldor,a Ed W. McLean,a
David Reynolds,a Douglas M. Sammond,a Andrew Spaltenstein,a Roger Tung,b
Elizabeth M. Turner,a Robert X. Xua and Ronald G. Sherrilla,*
aGlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
bVertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139, USA
Received 25 October 2005; revised 6 January 2006; accepted 6 January 2006
Available online 3 February 2006
Abstract—A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against
wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar
enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate
GW0385.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Despite over two decades of intensive research directed
toward the eradication of HIV/AIDS, the disease re-
mains a global health crisis. The epidemic is particularly
severe in the developing world, most notably sub-Saha-
ran Africa where there are currently estimated to be 25
million people living with HIV.1 Dramatic progress in
the treatment of HIV was realized in the mid-1990s with
the introduction of the HIV protease inhibitor class of
drugs. The inclusion of protease inhibitors (PIs) as a
component of highly active antiretroviral therapy or
‘HAART’ led to significantly improved clinical out-
comes and was quickly adopted as the standard of care
in HIV therapy.2 In addition to their well-documented
activity as potent inhibitors of viral polyprotein process-
ing, more recent research suggests that HIV PIs may
also play a role toward ameliorating protease mediated
cytopathogenesis in CD4+ T-cells.3 Although they have
seen considerable success in the management of HIV
disease, PIs have several significant shortcomings. Chief
among these is the emerging problem of drug resistance.
Viral strains that are resistant to the currently available
PIs have now developed and an increasing number of
patients are failing PI therapy.4 Therefore, the identifica-
tion of agents with activity against drug resistant viral
strains is of critical importance.
We recently reported three novel series of arylsulfona-
mide HIV-PIs obtained through iterative modification
of the amprenavir scaffold.5 Of these three series, the
class containing aminoalkyl chain extensions attached
to the para position of the P1 phenyl ring5a showed
the most promising antiviral activity against wild-type
virus and two PI-resistant viral strains (Fig. 1).
Herein, we describe our efforts to further optimize this
chemical series by exploring additional modifications in
the P1 position. In particular, we were interested in study-
ing the effect of attaching various aryl and heteroaryl moi-
eties to the P1 para oxygen atom. The diverse range of
properties afforded by this class of substituents should,
in principle, facilitate efficient lead optimization in this
series.
All compounds were generated through the previously
reported5a O-benzyl-protected, tyrosine-derived, inter-
mediate a. Catalytic hydrogenation of a over Pd/C yield-
ed phenolic intermediate b. Copper mediated aryl
boronic acid coupling of b employing conditions previ-
ously reported by Evans et al.6 provided diphenyl ether
analogs 1–6 in modest yields (Method B1). In general,
Keywords: Antiviral; Antiretroviral; Arylsulfonamide; Brecanavir;
Drug resistance; GW0385; HIV protease.
*
Corresponding authors. Tel.: +1 919 483 2750; fax: +1 919 483 6053
(J.F.M.), tel.: +1 919 483 6281; fax: +1 919 483 6053 (R.G.S.); e-mail
addresses: john.6.miller@gsk.com; ron.g.sherrill@gsk.com
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.035

J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
1789
Tables 1 and 2 illustrate the in vitro antiviral data for 27
new compounds in the P1 modified arylsulfonamide ser-
ies. For comparison purposes, Table 2 shows analogous
data for the structurally related competitor compound
TMC1147 and currently marketed PIs, also determined
in our in-house assays. The antiviral IC50s for wild-type
HIV virus (HXB2)8 and two multi-PI-resistant viruses
(EP13 and D545701, see Table 4) were determined in a
MT4 cell line.9
P1'
OH
P2
H
N
O
S
O
N
O
O
O
P2'
NH2
amprenavir
P1
Within the aryl ether sub-series 1–13 substitution on the
phenyl ring leads to modest increases in antiviral activity
regardless of the substitution pattern. A comparison of
the three isosteric derivatives 1, 6, and 7 is interesting.
The activity trends across the viral strains are similar
but the absolute potencies are greater for heteroaromat-
ic analogs 6 and 7. The aminomethyl-linked derivatives
9–13 show a general improvement in activity relative to
parent compound 1 and its simpler substituted deriva-
tives 2–5. The data for O-benzyl derivatives 14 and 15
indicate that insertion of a methylene unit into the ether
linkage of 1 yielded significant improvements in activity,
particularly against the mutant viruses. Chain extension
by an additional carbon atom, as exemplified by phen-
ethyl analog 16, leads to modest reductions in activity,
most notably against the D545701 strain. Interestingly,
the 2-substituted thiophene derivative 18 shows a 4-fold
improvement in activity as compared to its 3-substituted
congener 17. Triazole 19 and imidazole 23 show signifi-
cant reductions in wild-type activity, however, they
show increases in activity against the mutant strains ver-
sus wild type. A comparison of compounds 14 and 20
indicates that benzo ring fusion exerts a deleterious ef-
fect on activity. Pyridyl derivative 21 and quinoline 22
show a similar but less pronounced activity relationship.
As a class, thiazole derivatives 24–27 possess the most
impressive activities with single-digit nanomolar IC50s
against all three viral strains.
OH
H
O
H
N
O
S
N
O
O
O
O
O
H
O
P1
O
n
NHR
OH
H
H
N
O
S
O
N
O
O
O
O
O
H
O
OR
Figure 1.
ortho-substituted aryl boronic acids failed to couple as
did heteroaryl boronic acids excepting 3-pyridyl boronic
acid which provided analog 6, albeit in low yield. Ana-
log 8 was prepared via coupling of b with benzalde-
hyde-4-boronic acid prior to borohydride reduction of
the carboxaldehyde. Subsequent bromination of 8 and
amine displacement provided analogs 9 and 10. Alterna-
tively, displacement of the intermediate bromide with
ammonia followed by either acylation or sulfonylation
provided analogs 11–13 (Method C). Pyrimidine analog
7 was prepared through direct phenolic displacement of
2,4-dichloropyrimidine with b followed by catalytic
hydrogenation of the residual chloride (Method B2).
Cesium carbonate mediated alkylation of b in DMF at
room temperature with chloromethyl-substituted 2-pyr-
idine and 2-quinoline provided analogs 21 and 22
(Method B3), respectively. Substrates requiring elevated
temperatures gave rise to extensive degradation via oxa-
zolidinone formation with concomitant loss of the chiral
hydroxy furan. Therefore, prior protection of a as iso-
propylidene derivative c followed by benzyl deprotec-
tion, base-mediated alkylation, and final acid
hydrolysis was required to provide analogs 15, 20, and
27 (Method A). The remaining analogs were prepared
via Mitsunobu coupling of b with DtBAD, triphenyl-
phosphine, and the appropriate alcohol (analogs 16–19
and 23–26, Method B4) (Scheme 1).
Cellular antiviral activities are a composite of intrinsic
enzyme activity and intracellular transport efficiency.
In the absence of enzyme inhibition data, it is impossible
to know the relative contributions of these two factors in
determining antiviral activities. During the evolution of
our HIV PI program, we reached a level of enzyme
potency optimization at which the majority of com-
pounds being synthesized had inhibitor binding con-
stants below the lower limit (approximately 10 pM)
measurable using standard steady-state kinetics tech-
niques. As a result, the standard fluorometric assay10
was no longer useful in driving our lead optimization ef-
forts and we were forced to rely exclusively on cellular
antiviral data.
To address this problem, we developed a radioligand
binding assay which pushed the measurable Ki cutoff
down into the femtomolar range.11 However, due to
lower effective compound throughput, we employed this
assay not as a first line potency screen, but as a means of
determining enzyme activities for a limited number of
our more interesting lead molecules. Using this method,
compounds 21 and 27 were found to have enzyme Kis
against wild-type HIV protease of 6 and 15 fM,

1790
J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
O
OH
MeO OMe
H
H
H
N
PTSA, CH2Cl2, 60%
1.
O
S
O
O
N
N
O
N
O
O
S
O
O
O
O
O
O
O
O
H
O
H
O
2. 10% Pd/C, THF, 95%
c
a
OH
OBn
H2, 10% Pd/C
THF
Method A
98%
OH
OH
H
H
N
H
O
H
N
Method B
O
S
O
O
N
N
O
O
S
O
O
O
O
O
O
O
O
H
O
H
O
b
OHC
OR
OH
1.
B(OH)2
Cu(OAc)2, Pyr, 4Å sieves
46%
2. NaBH4, MeOH/THF
98%
OH
OH
H
H
H
H
O
S
O
O
N
N
O
O
N
N
Method C
O
S
O
O
O
O
O
O
O
H
O
H
O
O
8
O
O
N
R2
R1
OH
˚
Scheme 1. Reagents: Method A: (a) Cs2CO3, DMF, R-Cl; (b) HCl, H2O, dioxane. Method B: (1) Cu(OAc)2, pyridine, 4 A sieves or; (2) a–2,4-
dichloropyrimidine, EtOH, NaHCO3; b—5% Pd/C, EtOH, 2 M NH3 in MeOH or; (3) Cs2CO3, DMF, chloride or (4) Di-tert-butylazodicarboxylate,
PPh3, alcohol, CH2Cl2. Method C: PBr3, CH2Cl2, 46% then (1) 5 equiv amine, DMF or; (2) a—7 M NH3 in MeOH, 94%; b—acetyl chloride,
methanesulfonyl chloride or methyl chloroformate, DIEA, CH2Cl2.
respectively. These data indicate a remarkable level of
enzyme activity that ranges from 2400 to 6000 times that
of amprenavir. It is interesting to note the disparity be-
tween the amprenavir/27 enzyme differential (6000·)
and the analogous cellular antiviral differential (185X).
In addition, the data presented in Tables 1 and 2 indi-
cate a relatively weak correlation of antiviral activity
with the geometric and topological characteristics of
the various substituents at P1. Taken together, these
observations suggest that cell penetration may be a sig-
nificant if not limiting factor in dictating antiviral
activity.
modified derivatives and TMC114 against ClogP.12
The compounds with the best antiviral activities have
ClogP values in the 3.7–5.0 range (e.g., thiazoles 24–
27 and pyridine 21). Similar relationships were observed
for the wild-type and EP13 viral strains. The observed
functional dependence of biological activity on the
hydrophobicity descriptor ClogP suggests that mem-
brane transport is the dominant factor governing antivi-
ral activities in this compound series.
In the course of our lead optimization work in the P1
arylsulfonamide series, we examined a large number of
compounds for oral pharmacokinetics in rats and/or
dogs. The majority showed very low oral bioavailability
as determined in single dose experiments. However,
some did display modest % Fs in the 10–20% range.
Three selected examples are illustrated in Table 3. Thia-
zole derivative 27 yielded a 10% F and 20% F in rat and
dog, respectively. However, when 27 was co-adminis-
tered with 4 mg/kg of the cytochrome P450 (CYP450)
inhibitor ritonavir, these values increased to 62% F
and 86% F, respectively. Poor oral pharmacokinetics is
one of the most problematic aspects of HIV PI therapy.
To more rigorously address this possibility, we exam-
ined the relationship between antiviral activity and sev-
eral calculated physicochemical parameters (polar
surface area, ClogP, and molar volume) for the 27 com-
pounds in this study. While some limited correlation was
gleaned from the polar surface area numbers, a rather
well-defined relationship emerged between antiviral
activity and ClogP. No meaningful correlation was ob-
served between antiviral activity and molar volume.
Figure 2 shows a plot of D545701 IC50s for our P1

J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
standard error (n) for P1 modified diarylethers
1791
Table 1. Anti-HIV IC50
s
OH
H
H
O
S
O
N
N
O
O
O
O
O
H
O
OAr
Entrya
Ar
IC50 (nM)
EP13
Synthetic sequencec (yield)
b
HXB2
D545701
62 7 (6)
1
7.5 1.6 (6)
3.3 0.3 (5)
5.7 1.2 (5)
2.1 0.3 (5)
4.7 1.1 (5)
1.1 0.2 (5)
2.0 (1)
21 5 (6)
B1 (32%)
B1 (52%)
B1 (42%)
B1 (56%)
B1 (54%)
B1 (30%)
B2 (46%, 36%)
see Scheme 1
C1 (79%)
C1 (68%)
C2 (72%)
C2 (68%)
C2 (70%)
2
8.1 1.0 (5)
17 3 (5)
29 5 (5)
48 10 (5)
27 4 (7)
41 9 (5)
9.5 2.3 (6)
11 (1)
F
3
F
4
6.9 2.3 (7)
16 3 (5)
OMe
5
OMe
6
2.4 0.5 (5)
2.8 (1)
N
N
7
N
OH
N
8
1.6 0.4 (5)
1.2 0.2 (5)
2.8 0.2 (5)
6.2 1.2 (6)
7.2 1.1 (6)
1.3 0.2 (5)
1.6 0.4 (5)
2.9 0.6 (5)
4.6 0.4 (5)
3.4 0.6 (5)
5.3 1.0 (5)
2.2 0.4 (5)
8.4 1.1 (6)
13 2 (6)
19 3 (6)
6.3 0.9 (6)
11 2 (6)
6.8 1.3 (6)
9
O
10
11
12
13
N
NHAc
NHSO Me
2
NHCO Me
2
a All compounds were >95% pure by 1H NMR and HPLC.
b IC50, antiviral inhibition in MT-4 cell culture.
c See Scheme 1 for details.
In general, this problem is believed to be the result of a
combination of extensive CYP450-mediated first-pass
metabolism and variable cellular efflux by p-glycopro-
tein.13 Co-administration with sub-therapeutic doses of
ritonavir, also known as ‘pharmacoenhancement,’ has
been successfully employed to increase systemic drug
exposures in HIV PI therapy. The mechanisms by which
ritonavir ‘boosts’ drug exposures are believed to be
related to potent CYP450 inhibitory activity and possi-
bly to its ability to inhibit p-glycoprotein mediated cellu-
lar efflux. Based on its success over the last several years,
ritonavir-based PI boosting is now viewed as standard
clinical practice by most HIV clinicians.14
In order to more rigorously assess the potential of
analog 27 (GW0385) as a development candidate, the

1792
J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
standard error (n) for P1-tethered aryl analogs
Table 2. Anti-HIV IC50
s
OH
H
H
O
S
O
N
N
O
O
O
O
O
H
O
OR
Entrya
R
IC50 (nM)
EP13
Synthetic sequencec
b
HXB2
D545701
14
3.1 0.7 (6)
1.2 0.4 (3)
3.7 0.7 (6)
9.5 2.0 (6)
5.9 1.2 (6)
2.2 0.8 (3)
8.7 1.7 (5)
17 3 (6)
9.6 2.4 (7)
Ref. 5a
CN
15
2.2 0.6 (4)
25 5 (6)
A1 (46%)
B4 (72%)
B4 (44%)
B4 (71%)
B4 (59%)
A1 (92%)
B3 (60%)
B3 (44%)
B4 (81%)
B4 (38%)
B4 (25%)
B4 (47%)
A1 (36%)
16
17
44 12 (4)
11 2 (12)
12 2 (5)
S
S
18
2.3 0.5 (12)
21 3 (5)
3.4 0.6 (12)
8.3 0.8 (5)
30 4 (6)
N
N
19
N
20
11 1 (6)
59 16 (3)
4.5 0.6 (8)
19 3 (5)
N
21
1.2 0.5 (6)
2.5 0.6 (5)
69 10 (5)
0.9 0.2 (6)
1.9 0.3 (5)
0.6 0.2 (5)
0.7 0.1 (21)
1.2 0.3 (8)
5.2 1.2 (5)
20 3 (5)
N
22
H
N
23
16 3 (5)
N
N
S
24
1.5 0.5 (6)
2.5 0.2 (5)
1.2 0.2 (6)
1.1 0.1 (24)
5.1 1.0 (6)
6.5 1.4 (5)
3.5 0.4 (6)
4.8 0.5 (25)
S
25
N
N
26
S
N
27 (GW0385)
S
TMC114
—
—
—
—
—
—
—
—
3.9 1.6 (3)
25
40
6.8 3.2 (3)
93
32 10 (3)
70
—
—
—
—
—
—
—
—
Atazanavir
Lopinavir
Amprenavir
Saquinavir
Indinavir
400
440
80
>1000
>1000
603
130
60
50
330
450
>1000
440
>1000
>1000
Nelfinavir
Ritonavir
320
268
a All compounds were >95% pure by 1H NMR and HPLC.
b IC50, antiviral inhibition in MT-4 cell culture.
c See Scheme 1 for details.

J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
1793
468 amprenavir-resistant viral strain with an IC50 of
ꢀ8 nM. It is important to note that this broad-spectrum
antiviral resistance profile is in contrast to analogs
where even minor modifications were introduced at
P10, previously reported by our group.5b,5c For instance,
decreases in antiviral potency against the multi-PI resis-
tant D545701 strain in the N-alkoxy sulfonamides typi-
cally exceeded 20-fold.5b Figure 3 graphically depicts the
comparison of potency in the same panel between
GW0385 and currently marketed PIs along with
structurally related TMC 114, using a cutoff of 200 nM
for clarity. This comparison underscores the outstanding
potential for this class of inhibitors in treating HIV
patients infected with multi-PI resistant virus.
70
60
50
40
30
20
10
0
TMC-114
2.6
3.6
4.6
5.6
6.6
To fully investigate the effects of substitutions at P1, we
solved X-ray crystal structures for GW0385 complexed
in both the WT15 and D54570116 enzymes. Interestingly,
although a general collapse of the P1 pocket is observed
in the mutant enzyme, the P1 thiazolylmethyl tether is
able to adopt an angled conformation that appears to
produce an increase in van der Waals interactions with
hydrophobic elements of the mutant protein without
requiring additional hydrophilic interactions. This is
consistent with our observations regarding the influence
ClogP
Figure 2. Plot of D545701 antiviral IC50 versus ClogP.
Table 3. In vivo pharmacokinetic parameters for P1 modified
arylsulfonamides dosed at 1 mg/kg
Entry
Species
IV clearance
(mL/min/kg)
t1/2 (h)
% F
18
18
Rat
Dog
Rat
Rat
Rat
Dog
Dog
27
22
20
10
—
19
—
2.2
15
18
0.50
0.91
1.4
21
27
21
10
62a
27 + 4 mg/kg RTV
27
27 + 4 mg/kg RTV
1.1
0.87
1.2
20
86a
RTV, ritonavir.
a Calculated by dividing the ritonavir-boosted oral AUC by the non-
boosted IV AUC.
antiviral activity was examined in a more extensive pan-
el of clinical and engineered resistant viral strains con-
taining mutations in the aspartyl protease. Table 4 lists
the amino acid substitutions present in each resistant
virus along with antiviral activity as determined in
MT4 cells.
Impressively, GW0385 exhibited single digit nanomolar,
or less, potency against the entire screen. The largest
drop of potency was observed in the clinically derived
Figure 3. GW0385 antiviral resistance profile against current Pls.
Table 4. GW0385 resistance profile against PI-mutant virus
HIV-virus
Amino acid substitutions in the aspartyl protease gene
IC50 (nM)
HXB2–WT HIV-1
468 APV-r
0.7
8.2
I15V, E34G, M36I, S37E, I50V, L63P
L10I, L19Q, K20R, E35D, M36I, S37N, M46I, I50V, I54V, I62V, L63P, A71V, V82A, L90M
D545701 Multi PI-r
14330 NFV-r
30813 IDV-r
31246 Multi PI-r
EP13 Multi PI-r
EP14 Multi PI-r
Triple Multi PI-r
I50V
4.8
D30N, E35D, M36I, S37D, I62V, L64P, I64M, N88D
I15V, I54V, R57K, I62V, L63P, H69Y, A71T, I72E, V82A, I85V
0.45
0.46
1.7
L10I, I54V, L63P, A71V, I72V, V77I, V82A, I84V, L90M, Q92K
M46I, L63P, A71V, V82F, I84V
1.1
L10R, M46I, L63P, V82T, I85V
M46I, I47V, I50V
0.77
5.4
I50V
I54V
1.6
0.22
I54V
Abbreviations: NFV, nelfinavir; APV, amprenavir; IDV, indinavir.

1794
J. F. Miller et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1788–1794
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M. A. Antiviral Ther. 2004, 9, 301; (b) Boden, D.;
Markowitz, M. Antimicrob. Agents Chemother. 1998, 42,
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Kaldor, I.; Reynolds, D.; Sherrill, R. G.; Spaltenstein, A.
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of ClogP in this series where substituents that intro-
duced more hydrophilic character demonstrated a rela-
tive loss of antiviral potency. In addition, examination
of the mutant structure suggests that there may be water
mediated interactions between the thiazole nitrogen
atom of the inhibitor and Arg 8 and Asp 29 side chains
of the enzyme.
Following extensive preclinical testing, GW0385 suc-
cessfully entered clinical trials for the treatment of
HIV infection. The drug was generally safe and well tol-
erated. Pharmacoenhancement with ritonavir improved
exposures 33- to 85-fold in humans, depending on dose,
providing drug levels anticipated to be well above those
estimated to effectively inhibit resistant viruses.17
GW0385 (brecanavir18) has received fast track designa-
tion from the United States Food and Drug Administra-
tion and is currently being evaluated in Phase II studies
in HIV-infected patients.
6. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
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In summary, we have disclosed the synthesis and SAR
of a novel series of P1-substituted arylsulfonamides cul-
minating in the identification of the clinical candidate
GW0385. Outstanding antiviral activity against both
wild-type and mutant viruses, coupled with excellent
bioavailability obtained when co-dosed with the
CYP450 inhibitor ritonavir, highlights the therapeutic
potential of this next generation PI. GW0385 is expected
to proceed into Phase III clinical development for the
treatment of HIV in 2006.
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Acknowledgments
We acknowledge Wayne Schairer of Vertex Pharmaceu-
ticals for his contributions to our research program. We
would also like to acknowledge Ashley Jarvis, Stephen
Price, and David Wilkes of Oxford Asymmetry Interna-
tional for the preparation of a P1 compound set that
was employed in preliminary screening.
12. Daylight V.4.81, Daylight Chemical Information Systems,
Mission Viejo, CA.
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˚
15. 2.80 A, RCSB Protein Data Bank ID 2FDE.
˚
16. 1.58 A, RCSB Protein Data Bank ID 2FDD.
17. Ford, S.; Reddy, S.; Anderson, M.; Murray, S.; Ng-
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18. USAN approved only.