Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs

Article abstract of DOI:10.1016/j.bmcl.2009.07.118

The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A nov

Full text of DOI:10.1016/j.bmcl.2009.07.118

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5444–5448
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A)
for pharmacokinetic enhancement of drugs
a
a
a
Charles A. Flentge a, , John T. Randolph , Peggy P. Huang , Larry L. Klein ,
*
Kennan C. Marsh b, John E. Harlan c, Dale J. Kempf a
a Abbott Laboratories, Departments of Antiviral Research (D-R4CQ), Building AP-52, 200 Abbott Park Road, Abbott Park, IL 60064-3537, USA
b Exploratory Science (D-R4EK), Building Ap-9, 100 Abbott Park Road, Abbott Park, IL, 60064-3500, USA
c Structural Biology (D-R46Y), Building AP-10, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cyto-
chrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma
levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the
structural elements of RTV believed to be important to CYP3A inhibition, with general design features
being the attachment of groups that mimic the P2–P3 segment of RTV to a soluble core. Several analogs
were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably
with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A
and elevation of LPV was observed. The compounds described in this study may be useful for enhancing
the pharmacokinetics of drugs that are metabolized by CYP3A.
Received 22 May 2009
Revised 20 July 2009
Accepted 22 July 2009
Available online 30 July 2009
Keywords:
Cytochrome P450 3A
Ritonavir
Lopinavir
Ó 2009 Elsevier Ltd. All rights reserved.
The cytochrome P450 3A (CYP3A) group of enzymes is largely
responsible for the metabolic clearance of many important classes
of therapeutic agents, including immunosuppressants (i.e., cyclo-
sporin, FK506, rapamycin),1 the taxane derived chemotherapeutic
agents (e.g., taxotere),2 macrolide antibiotics (e.g., clarithromycin
and azithromycin),3 and the protease inhibitor class of antiretrovi-
ral agents (i.e., ritonavir (RTV), indinavir, saquinavir, amprenavir,
nelfinavir, lopinavir (LPV), tipranavir, atazanavir and darunavir).4
Compounds that inhibit CYP3A can increase the plasma levels of
these drugs through drug–drug interactions which may result in
adverse complications.3b,4a,5 However, when properly controlled,
pharmacokinetic enhancement of drugs can be beneficial to ther-
apy. Nowhere is this more evident than in the pharmacokinetic
boosting of inhibitors of HIV-1 aspartyl protease by RTV to treat
reducing the risk of resistance development.8 Pharmacokinetic
enhancement by RTV of other marketed HIV PIs also provides sig-
nificant clinical benefit.9
An analysis of RTV (Fig. 1) and close structural analogs identified
three important elements responsible for CYP binding and inhibi-
tion: (1) direct heme interaction via an unhindered electron-rich
atom (5-thiazole group), (2) extensive hydrophobic interactions
with the CYP active site and (3) stability toward CYP-mediated oxi-
dative chemistry.6 Spectroscopic studies have shown that one of
the structural features of RTV responsible for CYP binding and inhi-
bition is the unhindered nitrogen atom within the unsubstituted 5-
thiazolyl group, which is believed to bind directly to the CYP heme
iron.6 Metabolism of RTV by CYP3A occurs by hydroxylation of the
6
TM
HIV infection. The antiretroviral agent Kaletra is a co-formulation
of a second-generation protease inhibitor (PI), LPV7 with RTV, itself
a first generation PI. RTV is also a potent inhibitor of CYP3A
(Ki = 3.2 nM) and is administered at a sub-therapeutic dose suffi-
cient to inhibit the CYP3A-mediated metabolism of LPV, thereby
greatly enhancing exposure of LPV.4c The pharmacokinetic
enhancement of LPV by RTV allows for convenient dosing regimens
(both BID and QD are approved in the US) that maintain mean LPV
plasma levels >75-fold in excess of the EC50 for wild-type virus,
thereby improving the overall effectiveness of therapy by greatly
Ph
O
O
H
N
N
S
N
N
H
N
H
O
O
OH
N
S
Ph
Ritonavir
S
S
H
H
N
1
N
N
3'
3
O
N
O
N
R
2'
2
O
O
Ph
Ph
CYP3A inhibitor structure
* Corresponding author. Tel.: +1 847 937 7535; fax: +1 847 938 2756.
E-mail address: chuck.a.flentge@abbott.com (C.A. Flentge).
Figure 1. Design of novel CYP3A inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.118

C. A. Flentge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5444–5448
5445
isopropyl group on the 4-thiazole (at the opposite end of the mol-
ecule) to give the 2-hydroxyisopropyl derivative as the only major
metabolite found in human plasma.10 In this study, we used these
principles to design novel CYP inhibitors that are structurally less
complex, easier to prepare, more soluble than RTV, and devoid of
antiviral activity. These compounds are bi-functional inhibitors in
that they bear a 5-thiazole group at the terminus of two hydropho-
bic chains symmetrically positioned about a central amine. These
novel CYP inhibitors provide insight into strategies for designing
second-generation CYP inhibitors for enhancing and sustaining
levels of PIs, as well as other therapeutic CYP3A substrates.
Novel CYP inhibitors were designed (see Fig. 1) to take advan-
tage of these features by introducing two heterocycles containing
an unhindered nitrogen atom (e.g., 5-thiazole) that can be pre-
sented to the CYP heme iron while avoiding any alkylated hetero-
cycle which could possibly be oxidized by CYP3A. The heme-iron
binding heterocycle is presented at the terminus of a chain con-
taining groups designed to maintain good hydrophobic interac-
tions with the CYP active site. Since RTV has very low aqueous
solubility and requires extensive formulation to achieve oral
absorption,11 the heterocyclic groups were symmetrically placed
around a basic nitrogen to increase aqueous solubility.
The compounds were synthesized as shown in Schemes 1 and 2.
The protected amino alcohol 1 was oxidized to aldehyde 2, which
was subsequently allowed to react with amine and sodium triacet-
oxyborohydride to give the tertiary amine 3. This reductive amina-
tion reaction resulted in epimerization of the chiral centers, such
that 3 was obtained as a mixture of all possible stereoisomers.
Deprotection of 3, followed by reaction with the 4-nitrophenylest-
er of 5-hydroxymethyl thiazole (or other heterocycle) provided a
mixture of isomers, which could be separated by column chroma-
tography to give a 1:1 mixture of SS and RR isomers along with the
SR isomer.
Stereochemistry could be controlled by treating compound 1
with methanesulfonyl chloride to provide mesylate 4, which was
then converted to the corresponding azide and reduced by hydro-
genation with Lindlar’s catalyst to give amine 5. Aziridine 6, syn-
thesized from 1 by the action of triphenylphosphine and diethyl
azodicarboxylate, was treated with amine 5 to give the secondary
amine product 7 as a single diastereomer. Using this strategy, other
stereoisomers of 7 were readily prepared from the appropriate
enantiomer of 1.
Compound 7 was utilized in two separate synthetic pathways to
provide the target inhibitors as shown. Deprotection, followed by
bis-acylation gave 8, which was allowed to react with aldehyde un-
der reductive amination conditions to provide final compounds.
Alternatively, 7 was first converted to tertiary amine, followed by
deprotection and bis-acylation to give final compounds.
using cDNA-expressed CYP3A4 (supersomes).12 Tables 1–3 present
SAR for these compounds as inhibitors of recombinant human
CYP3A4. Table 1 shows SAR for compounds with different alkyl
substituents on the central nitrogen (N-1). All of these analogs
were potent CYP3A4 inhibitors, with only a threefold IC50 range
(0.05–0.15 lM) for groups ranging in size from hydrogen (8–10)
to the large chain present in the C3-symmetric inhibitor 11. The
stereochemistry of the benzyl side-chains at C-3 did not have a
large effect on activity, as can be seen by comparing the stereoiso-
mers of N-neopentyl (12 and 13), ethyl (15–17), and isobutyl (18–
20) analogs. N-Arylmethyl analogs (see 23–30) offered no potency
advantage over aliphatic analogs.
Table 2 presents SAR for various hydrophobic side-chains at
C-3. Compounds with smaller C-3 substituents such as compounds
31 (R = H) and 32–34 (R = methyl) showed markedly weaker CYP
inhibition, clearly demonstrating the importance of this group to
the activity of these compounds. The benzyl side-chain found in
compound 15 could be replaced with a group of similar or larger
size (for example, isobutyl analog 35) with little effect on the
CYP3A4 inhibitory potency.
The results in Table 3 indicate that replacement of the 5-thiaz-
olyl group at the chain terminus with other heterocycles resulted
in loss of activity against CYP3A4. The 5-oxazole 41, 5-imidazole
42, and 4-pyrazole 45 analogs were each ꢀ2-fold less active than
15. Removal of the nitrogen from the thiazole ring 43 resulted in
a fivefold loss in activity. Replacement of the thiazole with a basic
pyridyl group 44 resulted in a greater than 20-fold loss in activity.
Selected analogs were also evaluated for their ability to inhibit
the CYP3A4-mediated oxidation of 7-BQ in human liver micro-
somes (HLM).12 The inhibition data of the comparator compounds
is shown in Table 4. Inhibition in HLM was highly correlated to
inhibition in CYP3A supersomes (r2 = 0.78) (Fig. 2). The excellent
correlation between the data suggests that screening in cDNA-ex-
pressed CYP3A4 supersomes is a useful method for identification of
novel CYP3A inhibitors.
The inhibitory potencies of the CYP inhibitors against purified
recombinant HIV protease were evaluated following previously de-
scribed procedures.13 All CYP inhibitors prepared were found to
have activity (IC50) against HIV-1 protease >10 lM, which is
>50,000-fold weaker than RTV. These CYP inhibitors would there-
fore be expected to be devoid of antiviral activity.
Also in Table 4 are results for in vivo studies evaluating the abil-
ities of CYP inhibitors to enhance the plasma levels of LPV in dogs.
For these studies, equal doses of LPV and the CYP inhibitor (5 mg/
kg each) were administered by oral gavage in adult beagle dogs
(n = 3), and the concentrations of both compounds were simulta-
neously measured over time (12 time points over 12 h).6 In the ab-
sence of a CYP inhibitor, LPV gave no measurable plasma levels in
this model. The effect of all but one of the CYP inhibitors on boost-
ing plasma levels of LPV either equaled or exceeded the perfor-
These compounds were evaluated for their abilities to inhibit
the CYP3A4-mediated oxidation of 7-benzyloxyquinoline (7-BQ)
BocHN
Ph
CHO
BocHN
Ph
BocHN
Ph
NHBoc
Ph
(iii)
O
(ii)
(i)
OH
N
NO2
(iv)
N
O
O
1a
2a
3a
S
N
N
H
N
H
N
O
O
S
S
N
O
O
Ph
Ph
12
Scheme 1. Reagents and conditions: (i) (a) DMSO, ClC(O)C(O)Cl, CH2Cl2, ꢁ78 °C, 30 min; (b) Et3N, CH2Cl2, ꢁ78 °C—rt, 1 h; (ii) (CH3)3CCH2NH2, NaHB(OAc)3, AcOH, Cl(CH2)2Cl,
rt, 18 h; (iii) 1:2 TFA/CH2Cl2; (iv) EtOAc, 60 °C, 16 h.

5446
C. A. Flentge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5444–5448
Boc
BocHN
Ph
BocHN
Ph
BocHN
Ph
BocHN
Ph
NHBoc
Ph
(vi, vii)
(v)
(viii)
OH
N
OMs
NH2
N
H
+
Ph
N
6a
1a
4a
5a
7a
(ix)
N
NO2
O
N
H
N
H
N
O
O
O
O
S
S
S
N
O
O
(x)
Ph
Ph
15
Scheme 2. Reagents and conditions: (v) MsCl, Et3N, CH2Cl2, 0 °C, 2 h; (vi) NaN3, DMF, 80 °C, 2 h; (vii) H2, Lindlar’s catalyst, EtOH, 1 atm, rt, 3 h; (viii) 2-PrOH, 100 °C, 18 h; (ix)
(a) 1:2 TFA/CH2Cl2, rt, 2 h; (b) EtOAc, 60 °C, 16 h; (x) CH3CHO, Cl(CH2)2Cl, AcOH, NaHB(OAc)3, rt, 2 h.
Table 1
Table 2
SAR for substitution at N-1
SAR for hydrophobic side-chain substituents at C-3
S
N
S
S
S
H
N
H
N
H
N
H
1
N
1
N
N
N
N
3'
3
3
3'
O
O
O
N
O
2'
2
2'
2
O
R
Et
R
O
O
R
O
Ph
Ph
Compd
Stereo 3,30
R
CYP3A4a IC50
(lM)
Compd
Stereo 3,30
R
CYP3A4a IC50
(lM)
15
31
32
33
34
35
36
37
38
39
40
SS
CH2Ph
H
CH3
CH3
CH3
CH2CH(CH3)2
CH2CO2CH3
CH2(c-Hex)
CH2OCH2Ph
CH2(4-OH)Ph
CH2(4-OBn)Ph
0.15
>3
>3
RTV
8
9
0.05
0.148
0.09
SS
SR
RR
H
H
H
SS
SR
RR
SS
Mixture
Mixture
Mixture
Mixture
Mixture
1.79
1.33
0.136
0.088
0.066
0.135
0.091
0.3
10
0.099
Ph
O
11
S
0.065
O
N
H
N
12
13
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
SS,RR
SR
SS
SR
RR
SS
SR
RR
SS
RR
SS
SR
RR
SR
SS
SS
SS
CH2C(CH3)3
CH2C(CH3)3
CH2CH3
0.11
0.1
a
Inhibition of 7-BQ (CYP3A4).
0.15
0.11
0.11
0.11
0.09
0.067
0.052
0.05
CH2CH3
CH2CH3
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2(cPr)
(CH2)2CH(CH3)2
CH2Ph
Table 3
SAR for heterocycles at chain terminus
H
3'
N
H
N
1
3
Het
O
O
Het
N
2'
2
0.135
0.087
0.06
O
O
Et
Ph
Ph
CH2Ph
CH2Ph
Compd
Het
CYP3A4a IC50
(lM)
CH2(3-MeO)Ph
CH2(3-Pyr)
CH2(4-Pyr)
CH2(5-imidazole)
CH2(3-quinoline)
0.05
0.066
0.049
0.066
0.07
15
41
42
43
44
45
5-Thiazole
5-Oxazole
5-Imidazole
2-Thiophene
3-Pyridyl
0.15
0.274
0.348
0.741
3
SR
a
Inhibition of 7-BQ (CYP3A4).
4-Pyrazole
>0.3
a
Inhibition of 7-BQ (CYP3A4).
mance of RTV (LPV AUCs ranged from 10.23 to 22.95
11.26 g h/mL for RTV). Overall plasma levels of the novel CYP
inhibitors were somewhat lower than that observed with RTV in
this model (RTV AUC = 2.19 g h/mL vs AUC <2 g h/mL for all
compounds tested). The large C3-symmetric compound 11 gave
poor plasma levels, and was significantly less effective at enhanc-
ing plasma levels of LPV. The effect of the two stereoisomeric com-
pounds 12 and 13 on LPV levels was comparable to that for RTV.
Compounds 8 and 16 were the most effective at enhancing LPV lev-
els. Plasma levels of the secondary amine derivative 8 were higher
lg h/mL vs
Table 4, compounds bearing a larger alkyl group (i.e., neohexyl
analogs 12 and 13) were more potent inhibitors in vitro than those
bearing a smaller group (i.e., ethyl analog 16) or those lacking an
alkyl substituent (i.e., 8). In vivo, compounds bearing a smaller
group at this central nitrogen achieved higher plasma levels, with
the greatest overall exposure being achieved with the secondary
amine analog, 8.
A comparison between in vitro activity of CYP inhibitors and
their ability to boost LPV reveals an apparent inverse correlation
(Fig. 3a), such that the more potent inhibitors in vitro were less
effective at elevating LPV levels in vivo. The reason for this
observation may be twofold. Presumably, the relative potencies
against human CYP3A may not reflect the corresponding activi-
ties against the canine enzyme. Alternatively, CYP inhibition
l
l
l
than other compounds tested (AUC = 1.78
the greatest increase in the plasma levels of LPV (Cmax = 5.02
mL, AUC = 22.95 g h/mL).
l
g h/mL) and provided
lg/
l
The plasma exposures of this series appear to be related to the
substituent at the central nitrogen. As can be seen from the data in

C. A. Flentge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5444–5448
5447
Table 4
Effect of CYP inhibitors on plasma concentration of LPV in doga
Compd
CYP3A4b IC50
(lM)
HLM IC50
(l
M)
Mean (SEM) PK parametersc
LPV
CYP inhibitor
Cmax
AUC
Cmax
AUC
RTV
8
0.05
0.15
0.065
0.11
0.1
0.04
0.13
0.054
0.15
0.09
0.15
0.09
2.5
11.26
22.95
3.09
11.69
10.23
12.14
15.95
1.32
0.83
0.03
0.3
0.29
0.61
0.57
2.19
1.78
0.06
0.68
1.1
5.02
0.95
2.27
1.7
3.2
3.47
11
12
13
15
16
0.15
0.11
1.38
1.3
a
Oral co-dose of inhibitor and LPV (5 mg/kg each, n = 3).
Inhibition of 7-BQ (CYP3A4).
b
c
AUC (
l
g h/mL); Cmax
(
lg/mL).
may be relatively complete at concentrations achieved by each
inhibitor, and LPV exposure may depend on the exposure of
the boosting agent. This is supported by the high correlation of
CYP inhibitor exposure and LPV exposure (Fig. 3b). Thus, the
CYP inhibitors that achieved better exposure in vivo were more
effective at boosting LPV levels. These results reveal that CYP
inhibitors with relatively modest in vitro potency (in comparison
to the potent inhibitor RTV) can be very effective at boosting LPV
in vivo , provided they have favorable pharmacokinetic
properties.
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
This study has several limitations. In vivo screening was con-
ducted in dogs, while in vitro screening utilized human systems.
While the dog has proven to be a useful model for pharmacokinetic
enhancement of lopinavir, prediction of pharmacokinetic enhance-
ment in humans would require extensive additional in vitro stud-
ies in both canine and human systems. Nonetheless, the results
described here provide proof-of-concept that alternate CYP3A
inhibitors can be designed that may be useful for therapeutic
boosting.
0
0
0.05
0.1
0.15
0.2
Inhibition in HLM ( M)
µ
Figure 2. Correlation of CYP3A4 inhibition in HLM and recombinant CYP3A
supersomes.
25
In this report, we have described the design and synthesis of a
series of compounds that are potent inhibitors of cytochrome
P450 enzymes, based on structural elements found in the potent
CYP3A inhibitor RTV. These compounds are structurally less
complex than RTV and they have no activity towards HIV aspartyl
protease. Potent analogs in this series inhibit CYP3A with IC50
a
20
15
10
5
<0.1
0.05
l
l
M, comparing favorably to inhibition by RTV (IC50
M). Pharmacokinetic studies in dog demonstrate the ability
=
of these compounds to enhance plasma levels of LPV to an extent
that is equal to or greater than that achieved with RTV. Two com-
pounds, 8 and 16, co-dosed with LPV at 5 mg/kg each in dog, gave
the greatest pharmacokinetic enhancement of LPV, with LPV
0
0
0.05
0.1
0.15
0.2
CYP inhibitor IC50 ( M)
AUC = 22.95 and 15.95 lg h/mL, respectively. Results with these
µ
two compounds exceed that achieved with RTV, even though
plasma levels for 8 and 16 were both less than plasma levels of
RTV.
25
20
15
10
5
b
Acknowledgment
We thank Dr. David A. DeGoey for review and suggestions on
the manuscript.
Supplementary data
0
0
0.5
1
1.5
µ
2
2.5
Supplementary data (General experimental section: synthetic
procedures for preparation of compounds 2–45; cytochrome
P450 inhibition testing; pharmacokinetic analysis) associated with
this article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.07.118.
CYP inhibitor AUC ( g.hr/ml)
Figure 3. (a) Comparison of CYP inhibitor in vitro activity and LPV plasma level
achieved when co-dosed with the CYP inhibitor (5 mg/kg) in dog. (b) Comparison of
plasma levels achieved with co-dosing a CYP inhibitor and LPV (5 mg/kg) in dog.

5448
C. A. Flentge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5444–5448
6. Kempf, D. J.; Marsh, K. C.; Kumar, G. N.; Rodrigues, A. D.; Denissen, J. F.;
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