Novel Lopinavir analogues incorporating non-Aromatic P-1 side chains - Synthesis and structure-activity relationships

Article abstract of DOI:10.1016/S0960-894X(02)00643-1

The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1′ positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored.

Full text of DOI:10.1016/S0960-894X(02)00643-1

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3101–3103
Novel Lopinavir Analogues Incorporating Non-Aromatic P-1 Side
Chains—Synthesis and Structure–Activity Relationships
Hing L. Sham,* Chen Zhao, Leping Li, David A. Betebenner, Ayda Saldivar,
Sudthida Vasavanonda, Dale J. Kempf, Jacob J. Plattner and Daniel W. Norbeck
Pharmaceutical Discovery, R47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 10 June 2002; accepted 31 July 2002
Abstract—The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-10
positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure–
activity relationships explored.
# 2002 Elsevier Science Ltd. All rights reserved.
The HIV protease inhibitor Lopinavir1 (ABT-378) 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. The pseudo-C2-symmetrical dia-
mino-diphenylhexanol P-1/P-10 core unit of lopinavir is
identical to that of ritonavir2 and both have their struc-
tural roots in our early reports of C2-symmetric and
pseudo-C2-symmetric inhibitors of HIV protease, such
as compounds 1–43ꢀ5 shown in Figure 1.
Figure 1. HIV protease inhibitors.
*Corresponding author. Tel.: +1-847-937-1483; fax: +1-847-935-
5165; e-mail: hing.1.sham@abbott.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00643-1

3102
H. L. Sham et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3101–3103
The reduction of 8a to give 9a has been reported.6,7 The
reduction of 8b–f to provide the diamino compounds
9b–f followed similar procedures and is shown in
Scheme 2. The resulting amines were protected with a
Boc group. Catalytic debenzylation using transfer
hydrogenation provided the amines 10a–f. Coupling
of the amines with 2,6-dimethylphenoxyacetic acid8
using standard procedures provided 11a–f. Removal
of the Boc protecting group using trifluoroacetic acid
and coupling of the resulting amines with the cyclic
urea derived from L-valine8 provided the final pro-
ducts 12a–f.
Scheme 1. Synthetic scheme for the core unit. R: (a) benzyl, (b) butyl,
(c) isopropyl, (d) isobutyl, (e) 3-methylbutyl, (f) 2-ethylbutyl.
Inspection of the structures of the HIV protease inhibitors
in Figure 1 shows that all of them have the aromatic ben-
zyl group in both the P-1 and P-10 position. In order to
further desymmetrize the core unit and explore the result-
ing structure–activity relationships, we synthesized a series
of novel analogues of lopinavir in which the P-1 benzyl
side chain was replaced with non-aromatic alkyl groups.
The synthesis of the core unit with non-aromatic side
chains is shown in Scheme 1, following the same route
reported for the benzyl side chain.6 The key reaction,
treatment of the cyanomethyl ketone with a Grignard
reagent to give the corresponding enaminone, proceeds in
94% for benzyl Grignard. The alkyl Grignards used in
Scheme 1 give yields ranging from 82–91% for this trans-
formation.
The HIV protease inhibitory potencies2 (% inhibition
@ 0.5 nM) and the anti-viral activities (against the
cytopathic effects of HIVIIIB in MT-4 cells) of the
inhibitors 12a–f are reported in Table 1. The anti-
viral activities were assayed in the presence of 50%
human serum so as to better assess the effect of
plasma protein binding on activities. All the com-
pounds9 with alkyl side chains have enzymatic inhib-
itory potencies comparable to that of lopinavir.
However, in the anti-viral assay (in the presence of
50% human serum), lopinavir has the best potency.
In addition, its good pharmacokinetic profiles1 in
several animal species led to its selection as the can-
didate to enter clinical trials.
Scheme 2. Reduction of enaminone and synthesis of HIV protease inhibitors 12a–f.
Table 1. Inhibition of HIV protease and anti-viral activities in MT-4 cells
Compd
R
% Inhibiton @ 0.5 nM
Antiviral EC50,a mM
Cytotoxicity IC50, mM
12a (lopinavir)
Benzyl
Butyl
Isopropyl
Isobutyl
3-Methylbutyl
2-Ethylbutyl
93
87
93
64
97
87
0.10
0.92
0.26
0.32
0.34
2.8
17.8
32.9
56.2
34.4
18.7
17.8
12b
12c
12d
12e
12f
aIn the presence of 50% human serum.

H. L. Sham et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3101–3103
3103
Acknowledgements
4. Sham, H. L.; Wideburg, N. E.; Spanton, S. G.; Kohl-
brenner, W.; Betebenner, D. A.; Kempf, D. J.; Norbeck,
D. W.; Plattner, J. J.; Erickson, J. W. J. Chem. Soc., Chem.
Comm. 1991, 110.
We thank Dr. Stephen L. Gwaltney, II for his assistance
in the preparation of this manuscript.
5. Sham, H. L.; Zhao, C.; Stewart, K. D.; Betebenner,
D. A.; Lin, S.; Park, C.; Kong, X. P.; Rosenbrook, W., Jr.;
Herrin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.;
Molla, A.; Saldivar, A.; Marsh, K. C.; McDonald, E.;
Wideburg, N. E.; Denissen, J. F.; Robins, T.; Kempf, D. J.;
Plattner, J. J.; Norbeck, D. W. J. Med. Chem. 1996, 39,
392.
6. Stuk, T. L.; Haight, A. R.; Scarpetti, D.; Allen, M. S.;
Menzia, J. A.; Robbins, T. A.; Parekh, S. I.; Langridge, D. C.;
Tien, J.-H.; Pariza, R. J.; Kerdesky, F. A. J. J. Org. Chem.
1994, 59, 4040.
7. Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.;
Fitzgerald, M.; Hannick, S. M.; Kerdesky, F. A. J.; Menzia,
J. A.; Parekh, S. I.; Robbins, T. A.; Scarpetti, D.; Tien, J. H.
Org. Process Res. Dev. 1999, 3, 94.
8. Stoner, E. J.; Cooper, A. J.; Dickman, D. A.; Kolacz-
kowski, L.; Lallaman, J. E.; Liu, J. H.; Oliver-Shaffer, P. A.;
Patel, K. M.; Paterson, J. B.; Plata, D. J.; Riley, D. A.; Sham,
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References and Notes
1. Sham, H. L.; Kempf, D. J.; Molla, A.; Marsh, K. C.;
Kumar, G. N.; Chen, C.-M.; Kati, W.; Stewart, K.; Lal, R.;
Hsu, A.; Betebenner, D. A.; Korneyeva, M.; Vasavanonda, S.;
McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.; Niu, P.;
Park, O.; Jayanti, V.; Grabowski, B.; Granneman, G. R.; Sun,
E.; Japour, A. J.; Leonard, J. M.; Plattner, J. J.; Norbeck,
D. W. Antimicrob. Agents Chemother. 1998, 42, 3218.
2. Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.;
Betebenner, D. A.; Green, B. E.; McDonald, E.; Vasava-
nonda, S.; Saldivar, A.; Wideburg, N. E.; Kati, W. M.; Ruiz,
L.; Zhao, C.; Fino, L.; Patterson, J.; Molla, A.; Plattner, J. J.;
Norbeck, D. W. J. Med. Chem. 1998, 41, 602.
3. Kempf, D. J.; Marsh, K. C.; Paul, D. A.; Knigge, M. F.;
Norbeck, D. W.; Kohlbrenner, W.; Codacovi, L.; Vasava-
nonda, S.; Bryant, P.; Wang, X. C.; Wideburg, N. E.; Clem-
ent, J. J.; Plattner, J. J.; Erickson, J. Antimicrob. Agents
Chemother. 1991, 35, 2209.
9. All compounds reported have mass, NMR, and analytical
data consistent with the structures assigned.