Novel lopinavir analogues incorporating heterocyclic replacements of six-member cyclic urea - Synthesis and structure-activity relationships

Article abstract of DOI:10.1016/j.bmcl.2004.02.089

The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure-activity relationships explored.

Full text of DOI:10.1016/j.bmcl.2004.02.089

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2643–2645
Novel lopinavir analogues incorporating heterocyclic replacements
of six-member cyclic urea––synthesis and structure–activity
relationships
Hing L. Sham,* David A. Betebenner, William Rosenbrook, Thomas Herrin,
Ayda Saldivar, Sudthida Vasavanonda, Jacob J. Plattner and Daniel W. Norbeck
Pharmaceutical Discovery, R4MA Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 21 January 2004; accepted 13 February 2004
Abstract—The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in
which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure–activity relationships
explored.
Ó 2004 Elsevier Ltd. All rights reserved.
The human immunodeficiency virus (HIV) protease
inhibitor lopinavir1 (ABT-378, 1a) is the antiviral com-
ponent of KaletraTM (approved by FDA in September
2000), one of the latest approved HIV protease inhibi-
tors for the treatment of HIV infection. Lopinavir (1a)
possesses high potency against wild type and mutant
HIV proteases with Ki values ranging from 1.3–28 pM.2
The synthesis of lopinavir3 and its major metabolites,4
as well as structure–activity relationships of P-1 (benzyl
side chain),5 and P-20 (2,6-dimethylphenoxyacetyl)6
positions of lopinavir have been reported. In this report,
a series of lopinavir analogues in which the six-member
cyclic urea at position P-2 is replaced by various het-
erocycles is described. The synthesis and structure–
activity relationships of these analogues are reported.
The retrosynthetic analysis of lopinavir (1a) is shown in
Scheme 1. Coupling of the carboxylic acid 3a with amine
2 (synthesis of this amine is reported in Ref. 5) using
Scheme 1. Retrosynthetic schemes for lopinavir.
EDAC/HOBt provided 1a. Synthesis of lopinavir ana-
logues 1b–j are accomplished similarly by the coupling
of the novel carboxylic acids 3b–j with amine 2. The
synthesis of acids 3a–d is outlined in Scheme 2. Depro-
tection of compound 4 with trifluoroacetic acid, fol-
lowed by treatment with carbonyldiimidazole or
thiocarbonyldiimidazole provided compound 5 (60–75%
yield). Treatment of 5 (n ¼ 1, X ¼ O) with sodium
hydride, then methyl iodide resulted in 6 in 60% yield.
Hydrolysis of the methyl esters of 5 and 6 provided the
carboxylic acids 3a–d (85–92% yield).
The synthesis of acids 3e–g is illustrated in Scheme 3.
Refluxing the benzyl ester of L-valine with succinic
anhydride in chloroform gave 7 in 90% yield. Com-
pound 7 was treated with EDAC/HOBt in DMF in the
presence of 4-dimethylaminopyridine at room tempera-
ture for 4 days to cyclize to 8 (26% yield). Hydrogeno-
lysis of 8 provided acid 3e (95% yield). Reaction of
* Corresponding author. Fax: +1-847-938-1674; e-mail: hing.l.sham@
abbott.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.089

2644
H. L. Sham et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2643–2645
Scheme 2. Synthesis of acids 3a–d.
Scheme 4. Synthesis of acids 3h–i.
The synthesis of acids 3h–i is shown in Scheme 4.
Reaction of 4-bromobutanoyl chloride with -valine
L
methyl ester provided compound 11 in 86% yield.
Treatment of 11 with sodium hydride, provided c-lac-
tam 12. Hydrolysis of the methyl ester of 12 afforded
acid 3h (61% yield). Reaction of 13 with oxalyldiimi-
dazole in toluene, followed by hydrogenolysis gave 14
(35% yield), which was hydrolyzed to provide 3i. The
synthesis of acid 3j has been reported previously.
Coupling of the acids 3a–j with amine 2 provided lop-
inavir and its analogues 1b–j.
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–j are summarized in Table 1. Inhibitor 1c, with a five-
member cyclic urea, has very comparable activities to
lopinavir (1a), but has inferior pharmacokinetic (PK)
properties in rats, with a shorter half life (<0.5 h vs ꢀ1 h
for 1a, F% ¼ <15% vs 25% for 1a), and lower AUC than
1a. Removal of the hydrogen bonding capability of the
cyclic urea via N-methylation (1b), or replacing the
carbonyl with a thiocarbonyl (1d), or replacing the NH
with CH2 as in the case of lactam (1h), all seemed to
reduce the activities of the inhibitors. Substituting the
cyclic urea in 1a with both the five- or six-membered
cyclic carbamates reduced the activities only slightly.
Inhibitor 1j, though has the highest enzymatic potency,
is less active than 1a in the antiviral assay.
Scheme 3. Synthesis of acids 3e–g.
L
-valine benzyl ester with excess ethylene oxide in eth-
anol gave 9 (75% yield). Treatment of 9 with triphosgene
in methylene chloride, followed by hydrogenolysis
afforded acid 3f (70% for two steps). The mono-t-butyl-
dimethylsilyl group protected 1,3-propanediol was oxi-
dized with pyridinium sulfur trioxide in DMSO to give
the corresponding aldehyde, which underwent reductive
In summary, a series of HIV protease inhibitors in which
the six-member cyclic urea of lopinavir (1a) is replaced
by various heterocycles was synthesized. When com-
pared to the analogues synthesized (Table 1), lopinavir
(1a) has the best overall HIV protease inhibitory activ-
ity, antiviral potency, and pharmacokinetic profile in
amination with L-valine benzyl ester to provide 10 (63%
yield). Deprotection of 10 with in situ generated
hydrogen chloride (TMS–Cl/methanol) followed by
reaction with triphosgene and subsequent hydrogeno-
lysis furnished acid 3g in 70% yield.

H. L. Sham et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2643–2645
2645
Table 1. Inhibition of HIV protease and antiviral activities in MT-4
cells
several animal species, which led to its selection as the
clinical candidate to enter clinical trials.
O
H
O
N
N
Heterocycle
H
Acknowledgements
OH
O
We thank Dr. Qun Li for his assistance in the prepa-
ration of this manuscript.
1
Compound
Heterocycle7
%Inhibition
@ 0.5 nM
Antiviral
a
EC50 (lM)
O
1a (Lopinavir)
93
0.10
References and notes
N
N
NH
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.; 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. Nolla, A.; Vasavanonda, S.; Kumar, G. N.; Sham, H. L.;
Jahnson, M.; Grabowski, B.; Denissen, J. F.; Kohlbbren-
ner, W.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W.;
Kempf, D. J. Virology 1998, 250, 255.
3. Stoner, E. J.; Cooper, A. J.; Dickman, D. A.; Kolaczkow-
ski, L.; Lallaman, J. E.; Liu, J. H.; Oliver-Shaffer, P. A.;
Patel, K. M.; Paterson, J. B.; Plata, D. J.; Riley, D. A.;
Sham, H. L.; Stengel, P. J.; Tien, J. H. J. J. Org. Process
Res. Dev. 2000, 4, 264.
4. Sham, H. L.; Betebenner, D. A.; Herrin, T.; Kumar, G.;
Saldivar, A.; Vasavanonda, S.; Molla, A.; Kempf, D. J.;
Plattner, J. J.; Norbeck, D. W. Bioorg. Med. Chem. Lett.
2001, 11, 1351.
O
CH3
1b
1c
80
93
1.06
0.07
N
O
N
NH
S
1d
63
3.80
N
N
NH
O
1e
1f
58
87
85
87
2.51
0.11
0.27
0.31
O
O
5. Sham, H. L.; Zhao, C.; Li, L.; Betebenner, D. A.; Saldvarr,
A.; Vasavanonda, S.; Kempf, D. J.; Plattner, J. J.; Norbeck,
D. W. Bioorg. Med. Chem. Lett. 2002, 12, 3101.
6. Sham, H. L.; Betebenner, D. A.; Chen, X.; Saldivar, A.;
Vasavanonda, S.; Kempf, D. J.; Plattner, J. J.; Norbeck, D.
W. Bioorg. Med. Chem. Lett. 2002, 12, 1185.
N
O
O
1g
1h
N
O
7. All compounds reported have mass spectrum, NMR, and
analytical data consistent with the structures.
O
N
O
O
O
1i
1j
73
3.05
0.14
N
NH
100
N
NH
O
a In the presence of 50% human serum.