Synthesis and structure-activity relationships of a novel series of HIV-1 protease inhibitors encompassing ABT-378 (Lopinavir)

Article abstract of DOI:10.1016/S0960-894X(02)00134-8

The HIV protease inhibitor ABT-378 (Lopinavir) has a 2,6-dimethylphenoxyacetyl group in the P-2′ position. Analogues in which this group is replaced with various substituted phenyl or heteroaryl groups were synthesized and the structure-activity relationships explored.

Full text of DOI:10.1016/S0960-894X(02)00134-8

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1185–1187
Synthesis and Structure–Activity Relationships of a Novel
Series of HIV-1 Protease Inhibitors Encompassing
ABT-378 (Lopinavir)
Hing L. Sham,* David A. Betebenner, Xiaoqi Chen, Ayda Saldivar,
Sudthida Vasavanonda, Dale J. Kempf, Jacob J. Plattner and Daniel W. Norbeck
Pharmaceutical Discovery, D47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 11 January 2002; accepted 6 February 2002
Abstract—The HIV protease inhibitor ABT-378 (Lopinavir) has a 2,6-dimethylphenoxyacetyl group in the P-20 position. Analogues
in which this group is replaced with various substituted phenyl or heteroaryl groups were synthesized and the structure–activity
relationships explored. # 2002 Elsevier Science Ltd. All rights reserved.
The HIV protease inhibitor ABT-3781 (Lopinavir) is the
anti-viral component of KaletraTM (approved by FDA
in September, 2000), the latest approved HIV protease
inhibitor for the treatment of human immunodeficiency
virus (HIV) infection. ABT-378 (1a) possesses high
potency against wild-type and mutant HIV protease
(Ki=1.3–28 pM).1,2 The synthesis of ABT-3783 and its
major metabolites4 have been reported. At the P-20
position of ABT-378 is the 2,6-dimethylphenoxyacetyl
group, which is fairly lipophilic. In order to explore the
structure–activity relationship at this position, various
analogues of ABT-378 were synthesized. These analo-
gues possess different substitutions in the aryl or het-
eroaryl ring or the oxygen atom of the phenoxy linkage
is varied to sulfur and carbon. Following synthesis,
these compounds were tested to determine their inhibi-
tory potencies against HIV-1 protease and their
antiviral activities.
The retrosynthetic analysis for the synthesis of ABT-378
is shown in Scheme 1. Coupling of the key intermediate
2,6-dimethylphenoxyacetic acid (2a) with amine 3 using
Scheme 1. Retrosynthetic scheme for ABT-378 and key intermediates.
*Corresponding author. Fax: +1-847-935-5165; e-mail: hing.l.sham@abbott.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00134-8

1186
H. L. Sham et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1185–1187
Table 1. Inhibition of HIV protease and anti-viral activities in MT-4
cells
Compd
Ar
X
% inhibiton
@ 0.5 nM
Antiviral
a
EC50 (mM)
Scheme 2. Synthesis of acids 2a–l.
1a (ABT-378)
O
O
O
93
67
84
0.10
1.3
1b
1c
Phenyl
0.43
1d
1e
O
O
85
38
0.39
14
Scheme 3. Synthesis of acid 2m.
EDAC/HOBt provided ABT-378 (1a). Thus, the synth-
esis of various analogues of ABT-378 (1b–m) necessi-
tated the synthesis of acids 2a–m. The synthesis of acids
2a–l is shown in Scheme 2. The phenols and thiophenol
6a–i are commercially available and the phenols 6j–l
were synthesized according to literature procedures.5ꢀ7
Treatment of 6a–l with sodium hydride followed by
addition of ethyl 2-bromoacetate provided the corre-
sponding ethyl esters 7a–l (68–85%). Hydrolysis of the
esters with lithium hydroxide in aqueous THF gave
acids 2a–l. The synthesis of acid 2m is shown in
Scheme 3. Horner–Wadsworth–Emmons8 reaction of 2,6-
dimethylbenzaldehyde with triethylphosphonoacetate in
the presence of potassium t-butoxide provided the
a,b-unsaturated ester (89%). Hydrogenation followed
by hydrolysis provided acid 2m (90%). Coupling of the
acids 2a–m with the previously reported amine 3,3 using
EDAC/HOBt provided the HIV protease inhibitors 1a–m.
1f
O
O
O
S
87
86
37
55
79
90
75
70
2.8
0.16
38
1g
1h
1i
4.1
1j
O
O
O
C
4.2
1k
1l
0.49
0.77
2.6
The HIV protease inhibitory potencies (% inhibition @
0.5 nM) and the antiviral activities (against the cyto-
pathic effects of HIVIIIB in MT-4 cells) of the inhibitors
1a–m are reported in Table 1. Removal of one or two of
the methyl groups (1b and 1c) in the 2,6-dimethylphe-
noxyacetyl group of ABT-378 resulted in loss of
potency, as did addition of a 4-methyl group (1d).
Replacement of the 2,6-dimethyl substituents with 2,6-
dichloro (1f), 2,6-dimethoxy (1e), and 3,5-dimethyl (1h)
all resulted in significant loss of antiviral activity
(EC50’s, Table 1). We initially hypothesize that this
maybe due to the increase in lipophilicity and the
inability of these compounds to cross the cell membrane
effectively. However, although the clogP of 1f (6.3) is
greater than that of 1a (6.1), the clogP value of 1e (4.5)
and 1h (6.1) are actually lower or similar. This indicates
that lipophilicity is not the only factor that can affect
the anti-viral potency of these analogues. Increasing the
polarity of the analogues, such as in 1g (4-amino), 1k (4-
fluoro), and 1l (3-pyridyl) significantly restores the anti-
viral activity. The compound 1j (clogP=4.3) with
increased polarity, actually is significantly less potent in
its anti-viral activity when compared to 1a, further
demonstrating that lipophilicity/polarity is not the only
factor determining the antiviral potency. Replacement
1m
aIn the presence of 50% human serum.
of the ether oxygen in 1a with sulfur or carbon, as in
compounds 1i and 1m resulted in 25- to 40-fold loss of
anti-viral activity. Compared to the analogues9 shown
in Table 1, ABT-378 (1a) has the best HIV protease
inhibitory activity and antiviral potency. In addition, its
good pharmacokinetic profiles in several animal species
led to its selection as the clinical candidate to enter
human trials.
Acknowledgement
We thank Dr. Stephen L. Gwaltney, II for his assistance
in the preparation of this manuscript.

H. L. Sham et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1185–1187
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