Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands

Article abstract of DOI:10.1016/j.bmcl.2009.11.123

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers,

Full text of DOI:10.1016/j.bmcl.2009.11.123

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1241–1246
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1
protease inhibitors incorporating high affinity P2-ligands
a
a
a
b
c
Arun K. Ghosh a, , Sandra Gemma , Elena Simoni , Abigail Baldridge , D. Eric Walters , Kazuhiko Ide ,
*
Yasushi Tojo c, Yasuhiro Koh c, Masayuki Amano c, Hiroaki Mitsuya c,d
a Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States
b Departments of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States
c Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
d Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnors-
tatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, contain-
ing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties
and represent promising lead compounds for further optimization.
Received 19 October 2009
Revised 20 November 2009
Accepted 23 November 2009
Available online 5 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
HIV protease
Inhibitors
Darunavir
Allophenylnorstatine
Design
Synthesis
The introduction of protease inhibitors into highly active anti-
retroviral treatment (HAART) regimens with reverse transcriptase
inhibitors represented a major breakthrough in AIDS chemother-
apy.1 This combination therapy has significantly increased life
expectancy, and greatly improved the course of HIV management.
Therapeutic inhibition of HIV-1 protease leads to morphologically
immature and noninfectious viral particles.2 However, under the
selective pressure of chemotherapeutics, rapid adaptation of viral
enzymes generates strains resistant to one or more antiviral
agents.3 As a consequence, a growing number of HIV/AIDS patients
harbor multidrug-resistant HIV strains. There is ample evidence
that such strains can be readily transmitted.4 Therefore, one of
the major current therapeutic objectives has been to develop novel
protease inhibitors (PIs) with broad-spectrum activity against mul-
tidrug-resistant HIV-1 variants. In our continuing interest in devel-
oping concepts and strategies to combat drug-resistance, we have
reported a series of novel PIs including Darunavir, TMC-126, GRL-
06579, and GRL-02031.5–8 These inhibitors have shown exceed-
ingly potent enzyme inhibitory and antiviral activity as well as
exceptional broad spectrum activity against highly cross-resistant
mutants. Darunavir, which incorporates a (R)-(hydroxymethyl)-
sulfonamide isostere and a stereochemically defined bis-tetrahy-
drofuran (bis-THF) as the P2-ligand, was initially approved for
the treatment of patients with drug-resistant HIV and more re-
cently, it has been approved for all HIV/AIDS patients including
pediatrics9 (Fig. 1).
Darunavir was designed based upon the ‘backbone binding’ con-
ceptdevelopedinourlaboratories. Darunavir-boundX-raystructure
revealed extensive hydrogen bonding with the protease backbone
throughout the enzyme active site.10 The P2-bis-THF ligand is
responsible for its superior drug-resistance properties. The bis-THF
ligandhasbeendocumentedasaprivilegedligandfortheS2-subsite.
Incorporation of this ligand into other transition-state isosteres also
resulted in significant potency enhancement.11 Besides 3(S)-THF,
and [3aS,5S,6R]-bis-THF, we have designed a number of other novel
cyclic ether-based high affinity ligands. Incorporation of these li-
gands in (R)-(hydroxyethyl)-sulfonamide isosteres provided PIs
with excellent potency and drug-resistance properties.6–8 We then
investigated the potential of these structure-based designed P2-li-
gands in a KNI-764-derived isostere designed by Mimoto and co-
workers.12 This PI incorporates an allophenylnorstatine isostere.
Interestingly, KNI-764 has maintained good activity against HIV-1
clinical strains resistant to several FDA-approved PIs. The flexible
N-(2-methyl benzyl) amide P20-ligand may have been responsible
for its activity against drug-resistant HIV-1 strains as the flexible
chain allows better adaptability to mutations.12,13 The bis-THF and
other structure-based designed P2-ligands, make several critical
* Corresponding author. Tel.: +1 765 494 5323; fax: +1 765 496 1612.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.123

1242
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1241–1246
known optically active azidodiol 414 was first hydrogenated in
NH2
the presence of Boc2O. The resulting diol was converted to 5 by
selective acylation of the primary alcohol with acetic anhydride
in the presence of pyridine and a catalytic amount of DMAP at
0 °C for 4 h to provide 5 in 77% overall yield. As an alternative ap-
proach, commercially available optically active epoxide 6 was ex-
posed to lithium acetate, formed in situ from lithium carbonate
and acetic acid in DMF. This resulted in the regioselective open-
ing15 of the epoxide ring and afforded compound 5 in 62% yield.
The alcohol 5 thus obtained was protected as the corresponding
acetonide by treatment with 2-methoxypropene in the presence
of a catalytic amount of CSA. The acetate group was subsequently
hydrolyzed in the presence of potassium carbonate in methanol to
afford the corresponding alcohol. This was subjected to an oxida-
tion reaction using ruthenium chloride hydrate and sodium perio-
date in a mixture of aqueous acetonitrile and CCl4 at 23 °C for 10 h.
This resulted in the formation of the target carboxylic acid 7 in 61%
yield. Amide 9a was prepared by activation of carboxylic acid 7
into the corresponding mixed anhydride by treatment with isobu-
tylchloroformate followed by reaction with amine 8a.16,17
OH
H
H
N
O
H
N
O
S
O
O
O
O
H
Ph
1
, Darunavir
Ki =16 pM, EC50 = 1.6 nM
O
S
OH
H
N
N
O
HO
Me
H
O
NH Me
Ph
2
, KNI-764
S
OH
N
H
N
O
H
O
H
O
O
O
NH Me
Ph
O
Synthesis of various inhibitors was carried out as shown in
Scheme 2. Deprotection of the Boc and acetonide groups was car-
ried out by exposure of 9 to a 1 M solution of hydrochloric acid
in methanol at 23 °C for 8 h. This provided amine 10 in quantitative
3b (GRL-0355)
Ki = 5.2 pM, IC50 = 9.2 nM
Figure 1. Structures of inhibitors 1, 2, and 3b.
hydrogen bonds with the protein backbone, particularly with Asp-
29 and Asp-30 NH’s.11 Therefore, incorporation of these ligands into
the KNI-764-derived isostere, may lead to novel PIs with improved
potency and efficacy against multidrug-resistant HIV-1 variants.
Furthermore, substitution of the P2-phenolic derivative in KNI-764
with a cyclic ether-based ligand could result in improved metabolic
stabilityand pharmacological properties since phenolglucuronideis
readily formed when KNI-764 is exposed to human hepatocytes
in vitro.12
The synthesis of target compounds 3a–e was accomplished as
described in Scheme 1. Our synthetic plan for carboxylic acid 7
(Scheme 1) involved the preparation of the key intermediate 5
through two different synthetic pathways. In the first approach,
S
OH
a
H2N
Ph
N
O
9a
O
NH Me
O
H
10
O
O
O
N
O
b
O
O
11a
S
OH
H
H
N
O
N
O
O
O
NH Me
Ph
3a
OH
OH
BocHN
OAc
OH
a, b
N3
O
5
4
H
O
H
O
O
O
O
N
N
H
H
O
H
d-f
O
O
O
O
O
O
H
11b
11c
NO2
c
O
O
BocHN
BocN
OH
6
O
7
g
H
H
O
O
H
O
O
O
O
O
O
NO2
O
H
O
11d
11e
S
S
O
S
OH
HN
BocN
Ph
N
O
8a
H
N
RO
N
c
O
10
O
NH Me
NH Me
O
Ph
O
O
NH Me
9a
3b-e
Scheme 1. Reagents: (a) H2, Pd/C, Boc2O, EtOAc; (b) Ac2O, Pyr, DMAP; (c) LiCO3,
AcOH, DMF; (d) 2-methoxypropene, CSA, DCM; (e) K2CO3, MeOH; (f) RuCl3, NaIO4,
CCl4–MeCN–H2O (2:2:3); (g) N-methylmorpholine, iBuOCOCl, 8a, THF.
Scheme 2. Reagents: (a) 1 M HCl, MeOH; (b) 11a, Et3N, CH2Cl2; (c) 11b,c, Et3N,
CH2Cl2; or, 11d,e, DIPEA, THF.

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1241–1246
1243
yield. Reaction of 11a with amine 10 in CH2Cl2 in the presence of
Et3N at 23 °C for 6 h, provided inhibitor 3a in 62% yield. The 3(S)-
tetrahydrofuranyl carbonate 11a was prepared as described previ-
ously.18 Similarly, allophenylnorstatine-based inhibitors 3b–e
were synthesized. As shown, carbonates 11b,19 11c,7 and 11d–e19
were prepared as previously described. Reaction of these carbon-
ates with amine 10 furnished the desired inhibitors 3b–e in 45–
62% yield.
The syntheses of inhibitors 14a,b and 16a–c were carried out as
shown in Scheme 3. Inhibitors 14a,b, containing hydroxyethyl-
amine isostere were prepared by opening epoxide 6 with amine
8a in the presence of lithium perchlorate in diethyl ether at 23 °C
for 5 h to provide amino alcohol 12 in 64% yield. Removal of the
Boc-group by exposure to 1 M HCl in MeOH at 23 °C for 12 h affor-
ded amine 13. Reactions of amine 13 with activated carbonates 11a
and 11b afforded urethane 14a and 14b in 44% and 59% yields,
respectively. For the synthesis of inhibitors 16a–c, commercially
available (R)-5,5-dimethyl-thiazolidine-4-carboxylic acid was pro-
tected as its Boc-derivative. The resulting acid was coupled with
amines 15a–c in the presence of DCC and DMAP in CH2Cl2 to pro-
vide the corresponding amides. Removal of the Boc-group by expo-
sure to 30% trifluoroacetic acid afforded 8b–d. Coupling of these
amines with acid 7 as described in Scheme 1, provided the corre-
sponding products 9b–d. Removal of Boc-group and reactions of
the resulting amines with activated carbonate 11b furnished inhib-
itors 16a–c in good yields (55–60%).
Inhibitors 3a–e were first evaluated in enzyme inhibitory assay
utilizing the protocol described by Toth and Marshall.20 Com-
pounds that showed potent enzymatic Ki values were then further
evaluated in antiviral assay. The inhibitor structure and potency
are shown in Table 1. As shown, incorporation of a stereochemi-
cally defined 3(S)-tetrahydrofuran ring as the P2-ligand provided
inhibitor 3a, which displayed an enzyme inhibitory potency of
0.2 nM and antiviral IC50 value of 20 nM. The corresponding deriv-
ative 14a with a hydroxyethylamine isostere exhibited over 400-
fold reduction in enzyme inhibitory activity. Introduction of a ster-
eochemically defined bis-THF as the P2-ligand, resulted in inhibi-
tor 3b, which displayed over 40-fold potency enhancement with
respect to 3a. Inhibitor 3b displayed a Ki of 5.2 pM in the enzyme
inhibitory assay. Furthermore, compound 3b has shown an impres-
sive antiviral activity with an IC50 value of 9 nM. Inhibitor 14b with
hydroxyethylamine isostere is significantly less potent than the
corresponding norstatine-derived inhibitor 3b. Inhibitor 3c with
a (3aS, 5R, 6aR)-5-hydroxy-hexahydrocyclopenta[b]furan as the
P2-ligand has displayed excellent inhibitory activity, and particu-
larly, antiviral activity, showing an IC50 value of 13 nM. Other
structure-based designed ligands in inhibitors 3d and 3e have
shown subnanomolar enzyme inhibitory activity. However, inhib-
itor 3b with a bis-THF ligand has shown the most impressive
activity.
To obtain molecular insight into the possible ligand-binding site
interactions, we have created energy-minimized models of a num-
ber of inhibitors based upon protein-ligand X-ray structure of KNI-
764 (2).21 An overlayed model of 3b with the X-ray structure of 2-
bound HIV-1 protease is shown in Figure 2. This model for inhibitor
3b was created from the X-ray crystal structure of KNI-764 (2)-
bound HIV-1 protease (KNI-764, pdb code 1MSM21) and the X-ray
crystal structure of darunavir (pdb code 2IEN22), by combining the
P2-end of the darunavir structure with the P20-end of the KNI-764
structure, followed by 1000 cycles of energy minimization. It ap-
pears that both oxygens of the bis-THF ligand are suitably located
to form hydrogen bonds with the backbone atoms of Asp-29 and
Asp-30 NH’s, similar to darunavir-bound HIV-1 protease.10 Further-
more, the KNI-764-X-ray structure-derived model of 3b suggested
thatthe incorporationof appropriate substituentson the phenylring
could interact with Asp-290 and Asp-300 in the S20-subsite. In partic-
ular, it appears that a 4-hydroxymethyl substituent on the P20-phe-
nyl ring could conceivably interact with backbone Asp-300 NH in the
S20-subsite. Other substituents such as a methoxy group or an amine
functionality also appears to be within proximity to Asp-290 and
Asp-300 backbone NHs. Based upon these speculations, we incorpo-
rated p-MeO, p-NH2 and p-CH2OH substituents on the P20-phenyl
ring of inhibitor 3b. As shown in Table 1, neither p-MeO nor p-NH2
groups improved enzyme inhibitory potency compared to inhibitor
3b. Of particular note, compound 16a, displayed a good antiviral po-
tency, possibly suggesting a better penetration through the cell
membrane. Inhibitor 16c with a hydroxymethyl substituent showed
sub-nanomolar enzyme inhibitory potency but its antiviral activity
was moderate compared to unsubstituted derivative 3b. As it turned
out, inhibitor 3b is the most potent inhibitor in the series. We subse-
quently examined its activity against a clinical wild-type X4-HIV-1
isolate (HIV-1ERS104pre) along with various multidrug-resistant clin-
icalX4-andR5-HIV-1isolatesusingPBMCsastargetcells.5b Ascanbe
seen in Table 2, the potency of 3b against HIV-1ER104pre
(IC50 = 31 nM) was comparable to the FDA approved PI, amprenavir
with an IC50 value of 45 nM. Darunavir and atazanavir on the other
hand, are significantly more potent with IC50 values of 5 nM and
3 nM, respectively. Inhibitor 3b, while less potent than darunavir,
maintained 5-fold or better potency over amprenavir against HIV-
1MDR/C, HIV-1MDR/G, HIV-1MDR/TM and HIV-1MDR/MM. It maintained
over a 2-fold potency against HIV-1MDR/JSL. In fact, inhibitor 3b
maintained comparable potency to atazanavir against all
S
OH
a
6
BocHN
Ph
N
O
NH Me
12
b
S
OH
13
c
H2N
Ph
N
O
14a, b
NH Me
S
OH
d
7
BocHN
Ph
N
O
O
Me
NH Me
H2N
9b R = OMe
9c
R = NH2
R
9d R = CH2OH
R
15a R = OMe
15b
R = NH2
e
15c R = CH2OH
S
8b R = OMe
8c
16a R = OMe
16b
HN
O
R = NH2
8d R = CH2OH
NH Me
R = NH2
16c R = CH2OH
R
Scheme 3. Reagents: (a) 8a, Li(ClO4), Et2O; (b) CF3CO2H, CH2Cl2; (c) 11a or, 11b,
Et3N, CH2Cl2; (d) N-methylmorpholine, isobutylchloroformate, 8b-d, THF; (e)
CF3CO2H, CH2Cl2, then 11b, Et3N, CH2Cl2.

1244
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1241–1246
Table 1
Enzymatic inhibitory and antiviral activity of allophenylnorstatine-derived inhibitors
a,b
Entry
Inhibitor
Ki (nM)
IC50
(lM)
S
S
OH
H
H
N
O
N
O
O
O
O
O
1
0.21
0.02
NH Me
Ph
3a
OH
H
H
N
O
H
N
O
O
2
3
4
5
6
7
86.2
0.0052
2.6
nt
Ph
NH Me
14a
S
OH
H
N
O
H
N
O
H
H
O
O
0.009
Me
Me
Ph
O
NH
O
3b (GRL-0355)
S
OH
H
H
O
H
N
N
O
O
O
nt
Ph
NH
O
14b
S
OH
H
H
O
N
N
H
O
O
O
0.29
0.65
0.78
0.013
Ph
O
NH Me
H
3c
S
OH
H
N
H
O
N
O
H
O
O
O
nt
Me
Ph
NH
H
O
3d
S
OH
H
H
N
N
O
O
O
O
O
nt
Me
Ph
NH
S
O
3e
OH
H
H
O
H
N
N
O
O
Ph
O
H
8
Me
2.03
0.051
O
NH
O
16a
OMe

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1241–1246
1245
M)
Table 1 (continued)
a,b
Entry
Inhibitor
Ki (nM)
IC50
(l
S
OH
H
H
N
O
H
N
O
O
O
O
H
H
Me
Me
Ph
NH
NH
9
1.01
0.53
O
16b
NH2
S
OH
H
H
N
O
H
N
O
O
O
O
10
0.31
0.23
Ph
O
16c
OH
a
Values are means of at least three experiments.
Human lymphoid (MT-2) cells were exposed to 100 TCID50 values of HIV-1LAI and cultured in the presence of each PI, and IC50 values were determined using MTT assay.
b
Darunavir exhibited Ki = 16 pM, IC50 = 1.6 nM.
Figure 2. Structure of inhibitor 3b, modeled into the active site of HIV-1 protease, superimposed on the X-ray crystal structure of KNI-764. Inhibitor 3b carbons are shown in
green and KNI-764 carbons are shown in magenta.
Table 2
Antiviral activity of 3b (GRL-0355) against multidrug-resistant clinical isolates in PHA-PBMs.
Virus
IC50 (lM)
3b (GRL-0355)
APV
ATV
DRV
HIV-1ERS104pre (wild-type: X4)
HIV-1MDR/C (X4)
HIV-1MDR/G (X4)
HIV-1MDR/TM (X4)
HIV-1MDR/MM (R5)
HIV-1MDR/JSL (R5)
0.031 0.002
0.045 0.014
0.003 0.003
0.005 0.001
0.061 0.005 (2)
0.029 0.002 (1)
0.064 0.032 (2)
0.042 0.001 (1)
0.235 0.032 (8)
0.346 0.071 (8)
0.392 0.037 (9)
0.406 0.082 (9)
0.313 0.022 (7)
0.531 0.069 (12)
0.045 0.026 (15)
0.029 0.020 (10)
0.047 0.009 (16)
0.040 0.002 (13)
0.635 0.065 (212)
0.010 0.006 (2)
0.019 0.005 (4)
0.007 0.003 (1)
0.027 0.008 (5)
0.028 0.008 (6)
The amino acid substitutions identified in the protease-encoding region of HIV-1ERS104pre, HIV-1C, HIV-1G, HIV-1MM, HIV-1JSL compared to the consensus type B sequence cited
from the Los Alamos database include L63P; L10I, I15V, K20R, L24I, M36I, M46L, I54V, I62V, L63P, K70Q,V82A, L89M; L10I, V11I, T12E, I15V, L19I, R41K, M46L, L63P, A71T,
V82A, L90M; L10I, K14R, R41K, M46L, I54V, L63P, A71V, V82A, L90M; L10I, K43T, M46L, I54V, L63P, A71V, V82A, L90M, Q92K; and L10I, L24I, I33F, E35D, M36I, N37S, M46L,
I54V, R57K, I62V, L63P, A71V, G73S, V82A, respectively. HIV-1ERS104pre served as a source of wild-type HIV-1. The IC50 values were determined by using PHA-PBMs as target
cells and the inhibition of p24 Gag protein production by each drug was used as an endpoint. The numbers in parentheses represent the fold changes of IC50 values for each
isolate compared to the IC50 values for wild-type HIV-1ERS104pre. All assays were conducted in duplicate, and the data shown represent mean values ( 1 standard deviations)
derived from the results of two or three independent experiments. Amprenavir = APV; Atazanavir = ATV; Darunavir = DRV.
multidrug-resistant clinical isolates tested. The reason for its
impressive potency against multidrug-resistant clinical isolates is
possibly due to its ability to make extensive hydrogen-bonds with
the protease backbone in the S2 subsite and its ability to fill in the
hydrophobic pockets in the S10–S20 subsites effectively.
In conclusion, incorporation of stereochemically defined and
conformationally constrained cyclic ethers into the allophenyl-
norstatine resulted in a series of potent protease inhibitors. The
promising inhibitors 3b and 3c are currently being subjected to
further in-depth biological studies. Design and synthesis of new

1246
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1241–1246
9. (a) FDA approved Darunavir on June 23, 2006: FDA approved new HIV
treatment for patients who do not respond to existing drugs. Please see: http://
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108676.
htm (b) On October 21, 2008, FDA granted traditional approval to Prezista
(darunavir), co-administered with ritonavir and with other antiretroviral
agents, for the treatment of HIV-1 infection in treatment-experienced adult
patients. In addition to the traditional approval, a new dosing regimen for
treatment-naïve patients was approved.
classes of inhibitors based upon above molecular insight are cur-
rently ongoing in our laboratories.
Acknowledgement
The financial support of this work is provided by the National
Institute of Health (GM 83356).
10. Ghosh, A. K.; Chapsal, B. D.; Weber, I. T.; Mitsuya, H. Acc. Chem. Res. 2008, 41,
78–86.
11. Ghosh, A. K.; Ramu Sridhar, P.; Kumaragurubaran, N.; Koh, Y.; Weber, I. T.;
Mitsuya, H. ChemMedChem 2006, 1, 939–950.
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