Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.06.022

A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole- 6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent 'boosting' properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.

Full text of DOI:10.1016/j.bmcl.2012.06.022

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4998–5002
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers
of HIV protease inhibitors
⇑
Tim H. M. Jonckers , Marie-Claude Rouan, Geerwin Haché, Wim Schepens, Sabine Hallenberger,
Judith Baumeister , Jennifer C. Sasaki à
Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting
properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory
properties as well as overall ADME profile of these amide derivatives. This led to the identification of
thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-
hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together
with structurally similar analogues demonstrated excellent ‘boosting’ properties when tested in dogs.
These findings warrant further evaluation of their properties in an effort to identify valuable alternatives
to Ritonavir as pharmacokinetic enhancers.
Received 2 May 2012
Revised 8 June 2012
Accepted 10 June 2012
Available online 16 June 2012
Keywords:
Benzoxazoles
Benzothiazoles
Amides
Ó 2012 Elsevier Ltd. All rights reserved.
CYP3A4 inhibition
Boosting
The current options for the treatment of Human Immunodefi-
ciency Virus (HIV-1) infected patients consist of nucleoside ana-
logue reverse transcriptase inhibitors (NRTIs), protease inhibitors
(PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs),
CCR5 antagonists and a fusion inhibitor. A triple regimen compris-
ing NRTIs as a backbone regimen and NNRTIs and/or PIs is consid-
ered the standard of care.1,2 The use of PIs has been a major
breakthrough in the therapy for HIV-1 infection, substantially
reducing morbidity and mortality in infected individuals. The
majority of PI regimens involve co-administration of a low dose
of Ritonavir (NorvirÒ, RTV, 1) with the PI in order to enhance pa-
tient exposure to the latter agent, thereby preventing or overcom-
ing resistance and allowing less frequent dosing which potentially
improves patient adherence.3 RTV inhibits both the P-glycoprotein
(P-gp) transport system and the cytochrome P450 enzyme
CYP3A4.4 In contrast, the majority of PIs are metabolised by
CYP3A4 and most PIs are P-gp substrates. As a result, the pharma-
cokinetic profile of concomitantly administered PIs is beneficially
influenced in RTV boosted regimens, resulting in an increased bio-
availability of the boosted PI, slower elimination, and possibly,
improved penetration into HIV reservoirs may be achieved.
While 1 is approved as an HIV PI itself (600 mg, BID (=twice a
day)) it is hardly used as such, but more frequently as a pharmaco-
kinetic enhancer. Being the only approved pharmacokinetic enhan-
cer on the market, typical ‘boosting’ regimens contain a daily dose
of 100–200 mg of 1.
Unfortunately, the use of 1 is also associated with side effects
such as gastrointestinal adverse events and changes in serum lip-
ids, insulin resistance, lipoatrophy and CYP induction. Moreover,
since 1 is a PI itself, resistance mutations might be induced that
could contribute to resistance against other PIs. As a consequence,
novel derivatives devoid of the drawbacks associated with the use
of 1 are of major interest, and various groups have reported on
their progress in this area (Fig. 1).5–7 Cobicistat (2, GS-9350), a
compound structurally related to RTV has emerged recently as a
promising candidate. This compound has a comparable CYP3A4
inhibition to 1, but more importantly, shows an improved tolera-
bility and side effect profile. In addition, the superior physicochem-
ical properties of 2 compared with 1 allowed co-formulation with
tenofovir DF/elvitegravir/emtricitabine resulting in a single tablet
known as Quad which is being evaluated in a phase-III clinical trial
in HIV infected patients.8 Here, we report on our efforts aimed at
finding potential alternatives for 1. This communication describes
the discovery of a novel class of benzoxazole and benzothiazole
amides that were designed to have no other primary activity than
CYP3A4 inhibition together with an acceptable toxicity/side effect
profile. This exercise has led to the selection of C1, also named
TMC558445, as a lead candidate for the development of a new oral
pharmaco-enhancer of HIV PIs.
⇑
Corresponding author. Tel.: +32 (0)14 64 1168.
E-mail address: tjoncker@its.jnj.com (T.H.M. Jonckers).
Present address: Ablynx nv., Technologiepark 21, 9052 Zwijnaarde, Belgium.
Present address: Alkermes, Inc., 852 Winter St., Waltham, MA 02451-1420,
à
United States.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.022

T. H. M. Jonckers et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4998–5002
4999
R
N
S
OH
O
N
H
N
H
N
O
N
HN
S
N
N
H
N
R
O
O
Pfizer
Ritonavir (1)
O
N
N
O
H
H
O
R
S
O
N
N
O
O
N
N
O
S
S
N
R
O
O
R
Sequoia Pharmaceuticals
Abbott Laboratories
N
S
N
O
H
N
H
N
O
S
N
N
H
O
O
N
O
Cobicistat (2) / Gilead Sciences
Figure 1. RTV (1), Cobicistat (2) and other CYP3A4 inhibiting scaffolds.
Our search for novel CYP3A4 inhibitors started from 3, a previ-
ously identified PK-booster candidate which is also a potent HIV
protease inhibitor (Fig. 2).9 We based our design on three princi-
ples. First, we reasoned that preservation of the 5-thiazolyl moiety
might be crucial to ensure ample CYP3A4 inhibition. This structural
motif was identified as a major factor to explain the CYP3A4 inhib-
iting properties of 1 and related structures, as detailed spectro-
scopic studies showed that the N atom of the thiazole group is
able to interact directly with the iron atom present in the heme
group of CYP3A4. This interaction results in an impaired function-
ality of the enzyme.10,11 Secondly, we envisaged that modification
of the sulfonamide fragment of 3 would result in compounds
devoid of HIV protease inhibition since the interaction of the
sulfonamide group, either via the so called ‘flap water molecule’,12
or directly,13 with the backbone residues I50 and I500 of the HIV
protease is known to be essential for the class of sulfonamide
based HIV protease inhibitors.
Literature evidence shows that the modification or even com-
plete removal of the secondary OH group has been used for this
purpose given the crucial role this moiety plays in the interaction
with the D25 and D250 in the active site of HIV protease.7,8a How-
ever, switching from a sulfonamide group to an amide motif to
deliberately abolish the antiviral activity is clearly different from
any reported approach, and this concept is to the best of our
knowledge, unprecedented. Finally, we foresaw that optimization
of the R2-, R3- and R4-substituent would allow us the identification
of candidates with an optimal PK/PD profile.
A diverse set of derivatives was obtained using a convenient
synthesis that allowed easy alteration of all substituents (Scheme
1, Table 1). Our initial method started from commercially available
epoxides 4 that were reacted with an excess of primary amines 5
yielding derivatives 6a. Alternatively, we started from dibenzyl
protected intermediate 6b (where R2 = isopropyl, and R3 = Ph).
These were then coupled with acid derivatives 7 using HATU or
BOP as activating agent yielding intermediates 8.
Unexpectedly, the acid mediated deprotection of the Boc group
(TFA or HCl/iPrOH) resulted in the formation of undesired side and
decomposition products. Therefore, we reverted to a milder proce-
dure using trimethylsilylchloride/sodium iodide which allowed the
isolation of the amine after basic workup and purification by col-
umn chromatography.14 Base mediated coupling of intermediates
9 with activated carbonates 10 or 11 yielded the target compounds
C1 to C52.15 Contrary to the benzothiazole acid derivatives (7,
where X = S), the corresponding benzoxazole derivatives were
not commercially available. Therefore, starting from 4-amino-3-
hydroxybenzoic acid 12, the methylthio intermediate 13 was
N
O
NH2
O
S
O
O
N
H
N
O
N
S
OH
5-thiazolyl
group
(3)
R3
N
X
O
R4
O
C
OH R2
R1
O
N
H
N
Novel amide inhibitors
Figure 2. Design of new amide derivatives as CYP3A4 inhibitors.

5000
T. H. M. Jonckers et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4998–5002
N
R4
N
X
R3
R3
R3
R4
X
O
HOOC
7
R5
R5
R5
NH2
R2
N
N
N
+
N
NH
R5 OH R2
O
R5'
R5' OH R2
b
a
4: R5 = Boc, R5' = H
6a: R5 = Boc, R5' =H
5
8
6b: R5 = R5' = Bn,
R
2 = isobutyl
c
R3 = Ph
O
O
O
NO2
N
X
O
R3
N
X
N
R1
R3
O
R4
O
O
R1
O
R4
O
O
O
or
d
10
11
R1
O
N
H
N
H2N
N
OH R2
9
OH R2
C1-C52
Scheme 1. Reagents and conditions: (a) i-PrOH, reflux; (b) HATU or BOP, Et3N, CH2Cl2; (c) TMSCl, NaI, CH3CN or H2, Pd/C, MeOH; (d) Et3N, Me-THF, 10 or Et3N, Me-THF, DMAP,
11.
synthesized which served as an excellent precursor for various
benzoxazole amine derivatives 14 (Scheme 2). The aryl and alkyl
analogues were made via condensation of 12 with commercially
available orthoesters under microwave irradiation.
The in vitro antiviral activity of all new compounds against wild
type HIV-1 was evaluated in an acutely infected lymphoblastic cell
line (MT4-LTR-EGFP) using a reporter gene assay.16 As can be seen
from Table 1, none of the derivatives showed any significant activ-
Overall, having a 5-thiazolyl fragment (R1) present in the molecule
resulted, in most cases, in potent CYP3A4 inhibition, with the 3-
pyridyl and 5-benzo[1,3]dioxolyl fragment as good alternatives
(compare C1 with C4 and C10). On the other hand, the 4-pyridyl
group is clearly unfavorable as a 10-fold loss in inhibitory potency
was observed (C5). Furthermore, it was observed that the presence
of a basic nitrogen atom in the R2 and R4 substituents was not
desirable (see C6, C7 and C9) which directed our focus to less
hydrophilic alternatives. For the R4 substituent it was found that
also carbon linked substituents (see C11 and C13) as well as aro-
matic rings (C12 and C14) were tolerated. Moreover, the unsubsti-
tuted derivatives (R4 = H, C3 and C17) maintained good CYP3A4
inhibition. Finally, comparison of C1 with C15 showed that the ste-
reochemistry of the secondary OH group had no influence.
Based on their potent CYP3A4 inhibition, structural diversity as
well as physicochemical differences, we decided to study com-
pounds C1, C2 and C3 in more detail. First, the permeability and
affinity for efflux transporters of the three compounds was evalu-
ated in vitro, using a Caco-2 monolayer assay. As can be seen from
Table 2, compound C2 appeared to have the least attractive profile
ity against HIV WT with EC50 values >10 lM in all cases. As a com-
parison (3), which is the sulfonamide analogue of C8 has an EC50
value of 6.4 nM in this assay. These results thus confirmed that
the switch from the sulfonamide moiety to the amide had the
anticipated effect.
The CYP3A4 inhibition of all new compounds was determined
in vitro using a human liver microsomes (HLM) based assay in
which conversion of midazolam to 10-OH- midazolam was mea-
sured (by LC/MS) in the presence and absence of the inhibitor.
IC50 values shown in Table 1 were obtained by incubating the com-
pounds across a concentration range with HLM’s and the probe
substrate.17 Analysis of the results revealed several SAR trends.
Table 1
Structure, antiviral activity and CYP3A4 inhibition of selected benzoxazole and benzothiazole amide derivativesa,b
N
R3
R4
O
O
X
R1
O
N
H
N
OH R2
Compound R1
R2
R3
R4
X
Antiviral activity HIV-1 WT CYP 3A4 inhibition
(IIIB) (EC50
,
l
M)
(IC50, lM)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
5-Thiazolyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
2-(dimethylamino)ethyl Ph
2-(4-morpholinyl)ethyl
Isobutyl
Ph
Ph
Ph
Ph
Ph
Ethyl(methyl)amino
NH2
H
O
S
S
71
76
95
48
49
>100
>100
>100
>100
16
>100
13
45
0.031
0.019
0.023
0.022
0.2
0.41
0.14
0.042
2.7
0.044
0.052
0.024
0.037
0.024
0.022
0.023
0.090
5-Thiazolyl
5-Thiazolyl
3-Pyridyl
Ethyl(methyl)amino
Ethyl(methyl)amino
Ethyl(methyl)amino
Ethyl(methyl)amino
NH2
1-Methylpiperidin-4-ylamino
Ethyl(methyl)amino
Methyl
Phenyl
Isopropyl
4-Pyridyl
Ethyl(methyl)amino
Ethyl(methyl)amino
H
O
O
O
O
O
O
O
O
O
O
O
O
O
S
4-Pyridyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Isobutyl
5-Benzo[1,3]-dioxolyl Isobutyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
5-Thiazolyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
>100
45
47
4-F-Ph
3-Pyridyl
>100
a
Only SAR relevant derivatives C1–C17 are shown in this table. The data of other analogues (C18–C52) can be found in the Supplementary data file.
In all cases the stereochemistry of the C–OH chiral center is ‘R’ with the exception of C15 where it is ‘S’.
b

T. H. M. Jonckers et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4998–5002
5001
O
O
O
O
N
OH
OH
HO
R4
HO
O
a
b
NH2
NH2
R4 = aryl, alkyl
12
c, d
O
O
O
O
N
R
R
N
R'
O
N
O
N
O
O
HO
S
N
f
e
R'
13
14
Scheme 2. Reagents and conditions: (a) R4-C(OMe)3, W; (b) CH3COCl, MeOH; (c) C2H5OCS2K, pyridine; (d) MeI, K2CO3, EtOAc; (e) HNRR0, THF; (f) LiOH, THF/H2O.
l
Table 2
Apparant permeability (Papp) and efflux transporter affinity data for C1, C2 and C3 measured in Caco-2 cellsa
Compound
Permeability (Papp, 10-6 cm/s)
Transport polarity (Psecretory/Pabsorptive)
pH = 5.5
pH = 7.4
pH = 5.5
pH = 7.4
C1
C2
C3
10
0.52
11
11
1.2
9.8
2
26
2
2
22
3.6
a
Compounds were tested at 10 lM, measurements were done after 60 min of incubation.
Table 3
low permeability of the compound (Table 2) since the metabolic
stability for this compound in dog hepatocytes was found to
high.18 In rats, C3 showed the best oral PK profile while in dogs,
the overall exposure was found only to be similar to that of C1 not-
withstanding the fact that its Cmax value was 5-fold higher. Subse-
quently, we performed a drug–drug interaction (DDI) study in
dogs, to evaluate whether potent CYP3A inhibition and PK data
would occur and result in ‘boosted’ plasma levels of a co-adminis-
trated compound. For the latter, Darunavir (DRV) was chosen as a
probe molecule. DRV (PrezistaÒ, formerly known as TMC114) is an
HIV-1 protease inhibitor used for the treatment of naive as well as
treatment experienced HIV-1 infected individuals, first approved in
2006.16,19 The booster candidates C1, C2, or C3 were dosed orally at
7.5 mg/kg, 5 min prior to oral dosing of DRV which was given at
30 mg/kg. The effect of C1, C2, or C3 pre-administration on the
exposure and absorption of DRV was assessed by evaluating the in-
crease in Cmax and AUC values compared to when DRV was dosed
alone (Table 4).
PK parameters for C1, C2 and C3 following oral administration of a 10 mg/kg single
dose to rats and dogs (n = 3)a
Compound
Species
Cmax
g/mL)
Tmax (h)
AUC0–1
g.h/mL)
Fabs (%)
(
l
(l
C1
C2
C3
Rat
Dog
Rat
Dog
Rat
Dog
0.24
1.01
0.01
0.14
2.8
1.0
0.5
0.5
1.0
0.5
1.0
0.97
2.24
0.01
0.20
7.8
44
81
0.82
1.37
107b
97
5.2
2.24
Cmax = peak plasma concentration; Tmax = time point at which Cmax is reached;
AUC0–1 = area under the curve, total exposure; Fabs = absolute bioavailability.
aFormulation vehicles for all compounds were chosen based on solubility and tol-
erability; for C1: PEG400/2.5% VitE-TPGS (rat); PEG400/30% saline (dog). For C2:
20% hydroxypropyl-b-cyclodextrin (HP-b-CD) + 1% citric acid (rat) and 20% HP-b-CD
(dog). For C3: 20% HP-b-CD (rat & dog).
b
n = 2.
Gratifyingly, we learned that all three compounds had a signifi-
cant effect on the exposure of DRV as a 2-fold increase in Cmax and
a 5-fold increase in AUC was observed. Based on these data, none
of the candidates appeared to differentiate itself from the others
as the effects on the PK parameters of DRV were very similar for
the three compounds. However, we considered C1 as our preferred
candidate because the Cmax and AUC value were the lowest of the
since it showed to be poorly permeable and had high efflux trans-
porter affinity. In contrast, more favorable data were obtained for
C1 and C3.
Despite the clear differences between the compounds, we pro-
ceeded with a single dose PK experiment of C1, C2 and C3 in both
rats and dogs. In all cases, the animals were given an oral dose of
10 mg/kg. Table 3 summarizes the results.
In general, the exposure was higher in dogs compared to rats.
Compound C2 showed a less favorable oral pharmacokinetic profile
in both species, its overall exposure at this low dose being very
limited. The low AUC0–1-value for C2 can be attributed to the
three candidates (Cmax = 0.61 lg/mL; AUC0–1 = 2.0 l
g.h/mL).20
Overall, these findings suggest that C1 has an intrinsically better
profile as pharmaco-enhancer compared with the other two
candidates.
Table 4
Effect of the pre-administration of C1, C2 and C3 on the PK parameters of DRV in dogs (n = 3)
DRV Parameter
Compound pre-administereda
C1
C2
C3
Cmax
Fold increase
(
l
g/mL)
AUC0–1
(
lg.h/mL)
10.1
2.0
40.2
5.0
8.7
1.8
34.8
4.7
8.6
2.0
30.5
4.8
a
Compounds were dosed as PEG400 solution.

5002
T. H. M. Jonckers et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4998–5002
5. Sequoia Pharmaceuticals’ SPI-452: Gulnik, S.; Eissenstat, M.; Afonina, E.;
In conclusion, we have identified a novel class of CYP3A4 inhib-
Ludtke, D. et al. Preclinical and early clinical evaluation of SPI-452, a new
pharmacokinetic enhancer. 16th Conference on Retroviruses and Opportunistic
Infections (CROI): Montreal, 2009, Abstract 41. A benzofuran series was also
reported as PK enhancer; WO2008022345.
iting benzoxazole and benzothiazole amides that are devoid of HIV
protease inhibiting activity following a key ‘sulfonamide-to-amide’
switch. Three representative examples were shown to be capable
of substantially enhancing the plasma levels of DRV in dogs, mak-
ing them attractive lead candidates in the search for novel pharma-
cokinetic enhancers. The results of further evaluation of these
compounds on the pharmacokinetic profile of other HIV protease
inhibitors as well as on their general preclinical safety and toxicity
profile will be reported elsewhere.
6. Pfizer reported on pyrazole derivatives as Cyp450 inhibitors. See:
WO2008022345, WO2007034312, and WO2008004100.
7. Abbott Laboratories: Flentge, C. A.; Randolph, J. T.; Huang, P. P.; Klein, L. L.;
Marsh, K. C.; Harlan, J. E.; Kempf, D. J. Bioorg. Med. Chem. Lett. 2009, 19, 5444.
8. (a) Xu, L.; Liu, H.; Murray, B. P.; Callebaut, C.; Lee, M. S.; Hong, A.; Strickley, R.
G.; Tsai, L. K.; Stray, K. M.; Wang, Y.; Rhodes, G. R.; Desai, M. C. ACS Med. Chem.
Lett. 2010, 1, 209; (b) http://www.gilead.com/pipeline.; (c) tenofovir DF means
tenofovir disoproxil fumarate.
9. (a) Schueller, L.; Baert, L.; Lachau-Durand, S.; Borghys, H.; Clessens, E.; Van Den
Mooter, G.; Vangyseghem, E.; Jonckers, T. H. M.; Van Remoortere, P.; Wigerinck,
P.; Rosier, J. Int. J. Pharm. 2008, 355, 45.
Acknowledgments
10. Kempf, D. J.; Marsh, K. C.; Kumar, G. N.; Rodrigues, A. D.; Denissen, J. F.;
McDonald, E.; Kukulka, M. J.; Hsu, A.; Granneman, G. R.; Baroldi, P. A.; Sun, E.;
Pizzuti, D.; Plattner, J. J.; Norbeck, D. W.; Leonard, J. W. Antimicrob. Agents
Chemother. 1997, 41, 654.
11. For a general overview of Cytochrome P450 inhibition see: Lin, J. H.; Lu, A. Y. H.
Clin. Pharmacokinet. 1998, 35, 361.
12. King, N. M.; Prabu-Jeyabalan, M.; Nalivaika, E. A.; Wigerinck, P.; De Bethune, M.
P.; Schiffer, C. A. J. Virol. 2004, 78, 12012.
13. For an example of the direct sulfonamide interaction with I50 & I50’ see:
Nalam, M. N. L.; Peeters, A.; Jonckers, T. H. M.; Dierynck, I.; Schiffer, C. A. J. Virol.
2007, 81, 9512.
14. Rigby, J. H.; Wilson, J. Z. Tetrahedron Lett. 1984, 25, 1429.
15. At the end of this work, a third synthetic route was devised starting from 6b. In
this method, the thiazolyl carbamate was installed prior to the final HATU or
BOP mediated coupling which allowed modification of the amide moiety at the
end.
The authors gratefully acknowledge the collaborative and stim-
ulating support from Gerben Van ‘t Klooster, Piet Wigerinck, Dom-
inique Surleraux and Kurt Hertogs from the start-up to the
completion of this work. We also thank Leen Vandekerckhove,
Wim Van de Vreken, Maxime Canard, Rudy Strijbos, Bart Stoops
and Gery Dams for their technical assistance in the synthesis,
in vitro and in vivo characterization of the compounds and Kenny
Simmen for proofreading the manuscript.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
06.022.
16. Surleraux, D. L. N. G.; Tahri, A.; Verschueren, W. G.; Pille, G. M. E.; de Kock, H.
A.; Jonckers, T. H. M.; Peeters, A.; De Meyer, S.; Azijn, H.; Pauwels, R.; de
Bethune, M.; King, N. M.; Prabu-Jeyabalan, M.; Schiffer, C. A.; Wigerinck, P. B. T.
P. J. Med. Chem. 2005, 48, 1813.
17. (a) Compounds C1-C52 were also tested for their inhibition of other CYP
isoforms. C1 was found to also inhibit CYP2C9 and CYP2C19 while not
inhibiting CYP2D6 or CYP1A2. This data can be found in WO2009071650.
References and notes
(b) Ritonavir has an EC50 value of 0.0015
the practical setup of this assay can be found in the Supplementary data.
18. After hours of incubation with M of C2, only 12% of the dose was
metabolized in dog hepatocyte cultures.
19. McCoy, C. Clin. Ther. 2007, 29, 1559.
lM in this assay. More information on
1. (a) Bartlett, J. A.; DeMasi, R.; Quinn, J.; Moxham, C.; Rousseau, F. Aids 2001, 15,
1369; (b) MacArthur, R. D.; Novak, R. M.; Peng, G.; Chen, L.; Xiang, Y.; Hullsiek,
K. H.; Kozal, M. J.; van den Berg-Wolf, M.; Henely, C.; Schmetter, B.; Dehlinger,
M. Lancet 2006, 368, 2125.
2. (a) Cane, P. A. J. Antimicrob. Chemother. 2009, 64, i37; (b) Deeks, E. D.; Perry, C.
M. Drugs 2010, 70, 2315.
3. Xu, L.; Desai, M. C. Curr. Opin. Investig. Drugs 2009, 10, 775.
4. (a) Kumar, G. N.; Dykstra, J.; Roberts, E. M.; Jayanti, V. K.; Hickman, D.; Uchic, J.;
Yao, Y.; Surber, B.; Thomas, S.; Granneman, G. R. Drug Metab. Dispos. 1999, 27,
902; (b) Youle, M. J. Antimicrob. Chemother. 2007, 60, 1195.
2
2l
20. In comparison, for C2 and C3 these values were Cmax = 2.3
lg/mL & AUC0-1 =
6.48 g.h/mL and Cmax = 2.1 g/mL & AUC0-1 = 7.07 g.h/mL, respectively. The
l
l
l
increased exposure of C2 in the boosting studies could be related to the P-gp
inhibiting effect of DRV. Studies with the P-gp substrate taxol demonstrated
that DRV has P-gp inhibitory properties (internal report).