Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region

Article abstract of DOI:10.1016/j.bmcl.2013.12.058

Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.

Full text of DOI:10.1016/j.bmcl.2013.12.058

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationships of diamine inhibitors of cytochrome
P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region
a
a
a
c
b
Hongtao Liu a, , Lianhong Xu , Hon Hui , Randy Vivian , Christian Callebaut , Bernard P. Murray ,
Allen Hong a, , Melody S. Lee b, , Luong K. Tsai c, Jennifer K. Chau b, Kirsten M. Stray c, Carina Cannizzaro d,
You-Chul Choi a, , Gerry R. Rhodes b, Manoj C. Desai a
⇑
,
a Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA
b Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA
c Department of Biology, Gilead Sciences, Foster City, CA, USA
d Department of Structural Chemistry, Gilead Sciences, Foster City, CA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online xxxx
Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human
cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting
agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group
from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we
report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthe-
sis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the struc-
ture activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against
other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
Keywords:
CYP3A inhibitors
HIV-1 protease inhibitors
1,4-Diamines
Pharmacoenhancer
Selectivity against different CYP enzymes
Ó 2013 Elsevier Ltd. All rights reserved.
Protease inhibitors (PIs) of human immunodeficiency virus type
1 (HIV-1) are a key component of highly active antiretroviral ther-
apy (HAART) for the long-term management of HIV infection. The
introduction of ritonavir (RTV, 1) as a pharmacoenhancer for boost-
ing the pharmacokinetics (PK) of coadministered PIs represented a
new era of HIV treatment. RTV was originally licensed as a PI
(600 mg twice daily) and was later identified as a potent inhibitor
of human cytochrome P450 3A (CYP3A).1,2 Coadministration of low
dose RTV (usually 100–200 mg daily), results in significantly im-
proved PKs of concomitant PIs. This is a cornerstone of PI-contain-
ing regimens. The success of RTV as a pharmacoenhancer for PIs led
to its use with other antiretroviral agents metabolized by CYP3A.
2h,3 However, due to the inhibitory activity of RTV against HIV pro-
tease, there are concerns that using a subtherapeutic dose of RTV in
a PI-sparing regimen may select for RTV-resistant mutants, which
are known to induce cross-resistance to most drugs in the PI class.4
The potential of emergence of PI-resistance with sub-therapeutic
dose of RTV could therefore prevent future use of most PIs. In addi-
tion, RTV use is associated with side effects and complications,
including causing lipid disorders and triggering undesired drug
interactions, as an inducer of drug-metabolizing enzymes such as
CYP, p-glycoprotein (pgp), and UDP glucuronosyltransferases
(UGT).1 Thus, our goal was to identify a novel pharmacoenhancer
that maintains the same CYP3A inhibitory potency and mechanism
as RTV but lacks antiviral activity, and possesses an improved
safety profile and better physicochemical properties, such as solu-
bility, and is compatible with once-daily dosing.
Since RTV is a unique pharmacoenhancer that exerts sustained
pharmacological effects and has a record of long-term safety of
such effects demonstrated in clinical settings, our strategy was to
eliminate its anti-HIV activity while maintaining potent inhibitory
activity on CYP3A. Our initial attempts to eliminate the antiviral
activity of RTV were focused on the removal of the key hydroxyl
group which mimics the transition state of hydrolytic cleavage of
substrate through the formation of hydrogen bonds to the carbox-
ylate of the catalytic Asp25 and Asp225 residues at the active site
of the HIV protease.5 Two compounds (2a and 2b) were synthe-
sized. Desoxy-ritonavir (2a, desoxy-RTV) was obtained from RTV
by initial formation of a thiolester followed by subsequent free rad-
ical mediated deoxygenation (Scheme 1).6 As expected, compound
2a was less potent than RTV in a cell-based antiviral assay (EC50
0.29 M) but retained full inhibitory activity against CYP3A. Ke-
tone 2b, prepared from oxidation of RTV with Dess–Martin period-
inane, was an even weaker HIV-1 protease inhibitor (EC50
1.65 M) but still maintained CYP3A inhibitory activity. Compara-
:
l
:
l
tively, compound 2b has very poor physicochemical properties,
especially has a low solubility in both water and organic solvents,
therefore desoxy-RTV was chosen as our lead in subsequent
⇑
Corresponding author. Tel.: +1 650 522 5543; fax: +1 650 522 5899.
E-mail address: hongtao.liu@gilead.com (H. Liu).
These authors are no longer with Gilead Sciences.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.058
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2
H. Liu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Ph
activity much less than expected (only 3-fold), and was accompa-
O
O
H
N
nied with reduced CYP3A inhibitory potency (ꢀ3–5-fold), indicat-
ing the lipophilic interaction of RTV with protease contributes
greatly to its activity. The two benzyl groups of RTV interact with
the lipophilic S1 and S10 pockets of HIV protease, thus contribute
to its PI potency, so it was anticipated that modification of either
benzyl group could alter activity against HIV protease. The replace-
ment of either benzyl with an n-propyl (9d and 9e) reduced the
inhibitory activity against HIV by 2–5-fold. When both benzyl
groups were replaced with either ethyl (9f) or methyl (9g), the ana-
N
S
N
a or b
N
N
H
N
H
O
OH
O
S
Ph
1 ritonavir
core
Ph
O
O
H
N
2a R1, R2 : = H
2b R1R2 : = O
N
S
N
N
N
H
O
H
R1 R2
O
S
N
Ph
logs were inactive against HIV-1 (EC50 >30 lM). However, com-
Scheme 1. Synthesis of Compounds 2a/2b. Reagents and conditions: (a) (1) TCDI/
75 °C, (2) AIBN/Bu3SnH/115 °C; (b) Dess–Martin periodinane.
pound 9g has a 3-fold reduction in its inhibition of CYP3A as
well. It seems that the smallest size benzyl replacement at P1/P10
maintaining CYP3A activity is the ethyl. When the stereochemistry
of both benzyl groups was inverted from R,R- to S,S-, the compound
(9i) showed no anti-HIV-1 activity. To simplify the chemistry and
reduce the molecular complexity, both benzyl groups were either
eliminated (9j), or their attachments to the core were shifted to
nitrogen from carbon, which also eliminated the synthetic com-
plexity associated with the two chiral centers (9k). Both com-
pounds 9j and 9k were inactive against HIV protease since
elimination or relocation of the two benzyl groups disrupts their
interaction with S1 and S10 pockets. Compound 9k also eliminated
the hydrogen bond formation of the amines with the HIV protease
backbone. As observed with other anologs, compound 9j also dis-
played reduced ability to inhibit CYP3A, but it is notable that 9k
maintained this activity.
The physicochemical properties, especially aqueous solubility,
of RTV are poor, and one of our goals was to improve physicochem-
ical properties while generating novel CYP3A inhibitors. Polarity
and heteroatoms were introduced to increase the solubility of
the analogs. This could be readily designed-in by the introduction
of hydrazine in the core (9l and 9m). As shown in Scheme 3, hydra-
zine-containing analogs were prepared via a slightly modified syn-
thetic scheme. Carboxylic acid 8 was coupled with amine 10 to
give compound 11. The ester moiety of 11 was reduced to the cor-
responding alcohol, which was subsequently oxidized to aldehyde
12. Reductive amination of 12 with hydrazine 13, prepared from
hydrazine and p-nitrophenylcarbonate 3, provided compound 9l,
which was then treated with benzaldehyde under reducing condi-
tions to generate analog 9m. The profile of compound 9m against
CYP3A and HIV is similar to its carbon counterpart (2a), while com-
pound 9l lost activity against both enzymes.
To study the effect of core length on the anti-HIV activity and
CYP3A inhibitory potency, more analogs with different diamines
(1,2- or 1,3-diamines) were synthesized. These simple 1,2- or
1,3-diamines were either acquired from commercial sources, or
were synthesized following literature procedures. The synthesis
of the 1,3-diamine core of analogs 9r, 9s, 9t, 9u, and 9v is shown
in Scheme 4. Carboxylic acid 14a was esterified with iodomethane
to provide the corresponding methyl ester, which was then
reduced with lithium aluminium hydride (LAH) to alcohol 15a.
Alcohol 15a was converted to mesylate 16a, which was treated
with excess of the targeted amines to form compound 17a. The
synthesis of the 1,2-diamine core analogs 9aa and 9ab was similar
to that of 1,3-diamine core in Scheme 4, except starting from the
corresponding commercially available N-Boc-DL-phenylalaninol
15b in place of alcohol 15a. The 1,2-diamine core of analog 9z
was synthesized using a modified literature procedure from
Fokin.10 These mono-protected or unprotected 1,2- or 1,3-dia-
mines were converted to the final analogs following the same pro-
cedure for analogs with 1,4-diamine core shown in Scheme 2.
Consistent with the lower PI and anti-CYP3A activities observed
with 9g, it was not surprising that 1,3-diamine analogs lacking P1/
P10 moieties (9n, 9o, and 9p) showed reduced activity against both
HIV and CYP3A (Table 2). Re-installation of two benzyl moieties
structure–activity relationship (SAR) exploration. In this and the
following letter, we report our extensive SAR investigation towards
identification of novel human CYP3A inhibitors.7 Here we will de-
tail our SAR studies on the core portion of compound 2a.
It is interesting that 2a has limited reduction of anti-HIV activ-
ity; this serves to highlight the importance of optimized hydropho-
bic interactions contributing significantly to the HIV PI activity of
RTV. We next focused on modifications of the 1,4-diamine core.
Unsymmetric 1,4-disubstituted diamines were synthesized via a
sequence utilizing Julia olefination,8 while symmetric diamines
were prepared from an efficient synthesis newly developed by
us.9 N,N-Dibenzyl 1,4-diamines were produced by reductive ami-
nation of 1,4-butanediamine with benzaldehyde. A general route
for synthesis of analogs containing a modified diamine core is sum-
marized in Scheme 2. Reaction of diamine 4 with p-nitrophenylcar-
bonate 3 afforded monoamines 5. Urea formation via CDI coupling
of thiazolyl amine 6 and L-valine methyl ester 7 was followed by
subsequent ester hydrolysis to produce carboxylic acid 8. Com-
pound 9 was prepared through amide formation from acid 8 and
amine 5.
The CYP3A and HIV protease inhibitory activity data for these
compounds are summarized in Table 1. Compared to compound
2a, introduction of a rigid trans-double bond in the 1,4-diamine
core (9a) significantly reduced anti-HIV-1 activity (35-fold de-
crease). Compound 9h has a similar rigid backbone, and its 2,2-di-
methyl-1,3-dioxolane moiety likely interferes with its binding to
HIV protease, leading to significant loss of activity against HIV pro-
tease (EC50 >30 lM). It is known that both N–H groups of the 1,4-
diamine backbone of RTV form hydrogen bonds with Gly27/227 of
HIV protease. It was thus expected that introduction of a methyl
group (9b and 9c) on either nitrogen atom would be detrimental
to binding affinity for the protease. Both analogs reduced anti-HIV
O2N
O
O
a
S
N
S
N
O
O
H2N
X
N
H
O
core
3
5
H2N
X
4
NH2
O
N
OH
N
S
b
NH
+
N
N
H
OMe
H2N
HCl
O
S
O
O
6
7
8
core
X
O
H
N
S
N
O
N
c
N
N
H
H
N
5
O
S
9
Scheme 2. Synthesis of Compound 9. Reagents and conditions: (a) iPr2NEt; (b) (1)
CDI/iPr2NEt, (2) NaOH/MeOH; (c) HOBt/EDCI/iPr2NEt.
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H. Liu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 1
CYP3A activity and HIV protease activity of 1,4-diamine core compounds
core
X
O
O
H
N
S
N
N
H
O
N
S
N
N
H
O
H
(l
M)a
N
X
Compound
N
H
HIV protease IC50
0.0006
(l
M)
HIV replication EC50
0.015
(
lM)
CYP 3A IC50
0.11
1
Ritonavir
Ph
H
N
2a
2b
9a
9b
9c
0.005
ND
0.29
1.65
11
0.13
0.28
0.15
0.71
0.41
N
H
Ph
Ph
H
N
N
H
O
Ph
Ph
H
N
ND
N
H
Ph
Ph
N
H
N
ND
0.87
0.73
Ph
Ph
N
ND
N
H
Ph
H
N
9d
9e
N
H
ND
ND
1.7
0.13
0.13
Ph
Ph
H
N
0.55
N
H
H
N
9f
>30
>30
>30
>30
0.19
0.51
N
H
H
N
9g
N
H
Ph
O
H
N
O
9h
ND
>30
0.31
N
H
Ph
Ph
H
N
9i
>30
ND
>30
>30
>30
0.14
0.87
0.24
N
H
Ph
H
N
9j
N
H
Ph
N
9k
22.7
N
Ph
H
N
H
N
N
H
9l
8.8
>30
0.63
Ph
(continued on next page)
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H. Liu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1 (continued)
H
N
CYP 3A IC50 (l
M)a
X
N
H
Compound
HIV protease IC50
(l
M)
HIV replication EC50
(
lM)
Ph
H
N
N
9m
0.03
0.38
0.30
N
H
Ph
ND = not determined.
a
RTV and analogs are mechanism-based CYP3A inhibitors so representative IC50 values are provided; Inhibitory potency against midazolam 10-hydroxylase activity
catalyzed by CYP3A.7a
HCl
O
O
O
H
N
H
N
H2N
OH
N
N
S
b
CO2Me
a
N
N
O
N
H
CHO
N
N
H
N
N
H
CO2Me
O
+
O
O
S
Ph
O
S
Ph
Ph
11
8
10
12
Ph
O
O
O
H
H
N
H
N
N
H
N
N
N
S
N
N
S
N
d
c
N
N
H
N
H
N
N
H
O
O
S
O
S
Ph
Ph
9l
9m
O
O2N
O
e
S
H2N
N
H
O
S
N
O
O
N
3
13
Scheme 3. Synthesis of Compounds 9l and 9m. Reagents and conditions: (a) HOBt/EDCI/iPr2Net; (b) (1) LiBH4/THF/MeOH, (2) SO3ꢁpyridine/DMSO/Et3N; (c) 13/NaBH3CN/
HOAc/CH3CN; (d) PhCHO/NaBH3CN/TsOH/THF; (e) NH2NH2.
It is known that in addition to exhibiting inhibitory effects with
enzymes other than CYP3A, RTV activates the pregnane X receptor
COOH
BocHN
Ph
OH
BocHN
Ph
a
b
n
(PXR), the predominant regulator of CYP3A expression. Although
the net effect of RTV on human CYP3A clinically is inhibitory, this
inhibitory potency is reduced upon chronic dosing, as the rate of
CYP3A resynthesis is increased via induction. Other proteins in-
duced by RTV in vivo include CYP2B6, CYP2C9, CYP2C19, UGT1A4
(UGT 1 family, polypeptide A4) and p-gp, further complicating po-
tential drug–drug interactions.12 It is thus desirable to eliminate or
reduce this drug interaction potential for new pharmacoenhancers.
To understand this SAR, the inhibitory activity against different
CYP enzymes and PXR activation potential for selected analogs
were investigated. Data for a selected group of compounds are
listed in Table 3. Compounds 2a and 9f are structurally similar to
RTV, and they share similar profiles for CYP inhibition and PXR
activation. Compound 9i, the S,S-1,4-diamine core analog of 2a,
showed reduced PXR activation. Although compound 9k has rea-
sonable CYP3A selectivity and a simplified core, its PXR activation
potential is similar to that of RTV. It is interesting to note that 9r
and 9s possessed similar CYP profiles, and 9s had dramatically re-
duced PXR activation potential because of the change from isopro-
pyl at P2 site to the polar 2-morpholinoethyl moiety. Compound
9w had an even better PXR profile compared to 9s. Compound
9z, which has the short 1,2-diamine core, possessed the greatest
PXR activation potential of the compounds tested. From these data
it was apparent that the PXR activation potential could be modu-
lated with modifications of the backbone or through substituents
at the P2 moiety.
n
14a n = 1
14b n = 0
15a n = 1
15b n = 0
R
c
17a n =1
BocHN
Ph
OMs
n
BocHN
Ph
NH
R = Bn, iBu
n
2-ClBn,
4-ClBn
16a n = 1
16b n = 0
17b n = 0
R = Bn
Scheme 4. Synthesis of Compound 17. Reagents and conditions: (a) (1) MeI/KHCO3;
(2) LAH, 0 °C; (b) MsCl/pyridine; (c) RNH2/DMF.
either at both nitrogens, (9q) or one at carbon and the other at
nitrogen (9r) restored the CYP3A potency without adding HIV pro-
tease activity. The change of P2 isopropyl group to a 2-morpholino-
ethyl moiety (9s) did not alter the HIV protease or CYP3A
properties. Analogs with 4-chlorobenzyl, 2-chlorobenzyl, and iso-
butyl moieties at nitrogen (9t, 9u, 9v, and 9w) maintained similar
profiles. It was found that analogs with shorter, 1,2-ethanediamine
cores (9x, 9y, 9z, 9aa, and 9ab) showed parallel SAR for CYP3A inhi-
bition to analogs with the longer, 1,3-propanediamine core. From
the SAR in Table 2, it is clear that there are some minimum substit-
uents required to maintain CYP3A inhibitory activity.
We later provided our analogs with a variety of cores to Profes-
sor Poulos for studies with CYP3A4. The recent publication of the
crystal structure of CYP3A4 with RTV bound helps to explain some
of the SAR information described above.11 They noted the exten-
sive Van der Waals contacts between the phenyl rings of RTV
and the CYP3A4 apoprotein, and the contorted configuration of
the RTV backbone within the active site suggested that compounds
with more rigid cores would have reduced binding ability.
In summary, using desoxy-RTV 2a as the lead compound for de-
tailed SAR studies of the diamine core, we discovered several mod-
ifications that provide desirable profiles in terms of selectivity
against HIV activity, other CYP enzymes and PXR activation.
Compounds incorporating 1,4-diamine cores such as (2R,5R)-1,6-
diphenylhexane-2,5-diamine (18), (2S,5S)-1,6-diphenylhexane-
2,5-diamine (19), or (3S,6S)-octane-3,6-diamine (20) have
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H. Liu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 2
CYP3A activity and HIV protease activity of 1,3- or 1,2-diamine compounds
core
X
O
O
R
H
N
S
N
N
H
O
N
S
N
N
H
O
R
H
N
CYP 3A IC50 (l
M)a
X
Compound
N
H
HIV protease IC50
(lM)
HIV replication EC50
(l
M)
1
Ritonavir
0.0006
ND
0.015
>30
0.11
1.26
H
H
N
N
9n
N
9o
9p
ND
ND
4
9
1.84
1.67
N
H
N
H
N
Ph
N
Ph
9q
9r
21
>30
>30
0.30
0.32
N
Ph
H
N
N
ND
Ph
Ph
H
N
N
O
N
9s
9t
>30
>30
>30
>30
0.34
0.44
Ph
Cl
H
N
N
Ph
Cl
H
N
9u
>30
>30
0.34
N
Ph
H
N
N
9v
>30
>30
>30
>30
0.35
0.27
Ph
H
N
9w
N
Ph
H
N
9x
9y
ND
ND
>30
>30
1.1
1.4
N
H
N
N
Ph
H
N
9z
>30
>30
>30
>30
0.22
0.46
N
H
Ph
H
N
N
9aab
N
O
Ph
Ph
(continued on next page)
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6
H. Liu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 2 (continued)
R
H
N
CYP 3A IC50 (l
M)a
X
N
H
Compound
HIV protease IC50
(lM)
HIV replication EC50
(l
M)
H
N
N
9abb
>30
>30
0.5
Ph
Ph
ND = not determined.
a
RTV and analogs are mechanism-based CYP3A inhibitors so representative IC50 values are provided; Inhibitory potency against midazolam 10-hydroxylase activity
catalyzed by CYP3A.7a
b
Single compound but the absolute stereochemistry was not assigned, 9ab is an epimer of 9aa.
References and notes
Table 3
Evaluation of selectivity of pharmacoenhancers
1. Kempf, D. J.; Marsh, K. C.; Kumar, G.; Rodrigues, A. D.; Denissen, J. F.; McDonald,
Compound
CYP enzyme IC50
(l
M)
PXR activation7a (%)
E.; Kukulka, M. J.; Hsu, A.; Granneman, G. R.; Baroldi, P. A.; Sun, E.; Pizzuti, D.;
Plattner, J. J.; Norbeck, D. W.; Leonard, J. M. Antimicrob. Agents Chemother. 1997,
41, 654.
3A
1A2
2C19
2C9
2D6
2. For reviews on boosted PI see following reviews and references therein: (a)
Gerber, J. G. Clin. Infect. Dis. 2000, 30, S123; (b) Moyle, G. J.; Back, D. HIV Med.
2001, 2, 105; (c) Cooper, C. L.; van Heeswijk, R. P. G.; Gallicano, K.; Cameron, D.
W. Clin. Infect. Dis. 2003, 36, 1585; (d) Becker, S. L. Expert Opin. Invest. Drugs
2003, 12, 401; (e) Gallant, J. E. AIDS Rev. 2004, 6, 226; (f) Youle, M. J. Antimicrob.
Chemother. 2007, 60, 1195; (g) Busse, K. H.; Penzak, S. R. Expert Rev. Clin.
Pharmacol. 2008, 1, 533; (h) Xu, L.; Desai, M. C. Curr. Opin. Investig. Drugs 2009,
10, 775.
RTV
2a
9f
9i
9k
9r
9s
9w
9z
0.11
0.13
0.19
0.14
0.24
0.32
0.34
0.27
0.22
>25
>25
>25
10
>25
>25
>25
>25
22.9
12.7
9.3
7.8
>5
1.5
>25
6.7
>25
8.7
4.9
6.8
2.3
2.9
6.5
0.4
1.1
0.9
1.3
8.1
2.3
51
60
55
27
52
83
21
9.4
100
13.4
13.8
3.4
>25
8.1
>25
>25
3. DeJesus, E.; Berger, D.; Markowitz, M.; Cohen, C.; Hawkins, T.; Ruane, P.; Elion,
R.; Farthing, C.; Zhong, L.; Cheng, A. K.; McColl, D.; Kearney, B. P. J. Acquir.
Immune Defic. Syndr. 2006, 43, 1.
4. Hertogs, K.; Bloor, S.; Kemp, S. D.; Van den Eynde, C.; Alcorn, T. M.; Pauwels, R.;
Van Houtte, M.; Staszewski, S.; Miller, V.; Larder, B. A. AIDS 2000, 14, 1203.
5. For illustration that ritonavir binds with HIV protease, see Kempf, D. J.; Marsh,
K. C.; Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.;
Fino, L.; Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W.
M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.;
Norbeck, D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484.
6. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
7. (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) Xu, L. Abstracts of Papers, 239th ACS National Meeting,
San Francisco, CA. March 21–25, 2010.; (c) Liu, H.; Xu, L.; Hong, A.; Hui, H.;
Vivian, R.; Murray, B.; Callebaut, C.; Lee, M.; Tsai, L.; Stray, K.; Chau, J.; Rhodes,
G. R.; Desai, M. C. Abstracts of Papers, 239th ACS National Meeting, San
Francisco, CA. March 21–25, 2010.
favorable overall profiles. Further modifications on (2R,5R)-1,6-
diphenylhexane-2,5-diamine core (18) were made to improve
selectivity as a CYP3A inhibitor. These diamine cores had been
used as a basis for further discovery of novel CYP3A inhibitors,
and the results of which will be discussed in the following letter.13
Ph
Ph
8. (a) Gurjar, M. K.; Pal, S.; Rao, A. V. R.; Pariza, R. J.; Chorghade, M. S. Tetrahedron
1997, 53, 4769; (b) Rao, A. V. R.; Gurjar, M. K.; Pal, S.; Pariza, R. J.; Chroghade, M.
S. Tetrahedron Lett. 1995, 36, 2505.
9. Xu, L.; Desai, M. C.; Liu, H. Tetrahedron Lett. 2009, 50, 552.
10. Whiting, M.; Tripp, J. C.; Lin, Y.-C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.;
Sharpless, K. B.; Fokin, V. V. J. Med. Chem. 2006, 49, 7697.
H2N
Ph
H2N
Ph
H2N
NH2
NH2
NH2
18
19
20
11. Sevrioukova, I. F.; Poulos, T. L. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 18422.
12. (a) Kharasch, E. D.; Mitchell, D.; Coles, R.; Blanco, R. Antimicrob. Agents
Chemother. 2008, 52, 1663; (b) Foisy, M. M.; Yakiwchuk, E. M.; Hughes, C. A.
Ann. Pharmacother. 2008, 42, 1048.
13. Xu, L.; Liu, H.; Hong, A.; Vivian, R.; Murray, B. P.; Callebaut, C.; Choi, Y.-C.; Lee,
M. S.; Chau, J.; Tsai, L. K.; Stray, K. M.; Strickley, R. G.; Wang, J.; Tong, L.;
Swaminathan, S.; Rhodes, G. R.; Desai, M. C. Bioorg. Med. Chem. Lett. 2014.
http://dx.doi.org/10.1016/j.bmcl.2013.12.057.
Acknowledgment
We thank Swami Swaminathan and Tomas Cihlar for their sup-
port during the work.
Please cite this article in press as: Liu, H.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2013.12.058