The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor

Article abstract of DOI:10.1021/ml100029k

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization

Full text of DOI:10.1021/ml100029k

pubs.acs.org/acsmedchemlett
The Discovery of Setileuton, a Potent and Selective
5-Lipoxygenase Inhibitor
^
Yves Ducharme,* Marc Blouin, Christine Brideau, Anne Chateauneuf, Yves Gareau,
ꢀ ꢁ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
Erich L. Grimm, Helene Juteau, Sebastien Laliberte, Bruce MacKay, Frederic Masse,
Marc Ouellet, Myriam Salem, Angela Styhler, and Richard W. Friesen
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1
ABSTRACT The discovery of novel and selective inhibitors of human 5-lipoxy-
genase (5-LO) is described. These compounds are potent, orally bioavailable, and
active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major
focus of the optimization process was to reduce affinity for the human ether-a-
go-go gene potassium channel while preserving inhibitory potency on 5-LO. These
efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a com-
pound selected for clinical development for the treatment of respiratory diseases.
KEYWORDS Human 5-lipoxygenase, leukotriene biosynthesis, MK-0633, setileuton,
respiratory diseases
eukotrienes (LTs) are potent lipid inflammatory media-
tors derived from arachidonic acid metabolism and
released from cells involved in the inflammatory pro-
effectiveness. Thus, COPD could be another indication for
inhibitors of 5-LO.9 Accumulating evidence suggests that
5-LO inhibitors could also be useful for the treatment of athero-
sclerosis,10 pain,11 and cancer.12 Herein, we describe the design
of a novel series of coumarin analogues demonstrating high
potency at inhibiting 5-LO, leading to the identification of
(S)-16 (MK-0633, setileuton) as a development candidate.
Our effort started with phenylthioether 2 (Table 1), a 5-LO
inhibitor identified in a previous research campaign.13 This
compound shows a high potency at inhibiting calcium
ionophore-stimulated production of LTB4 in human whole
blood (HWB) in vitro, with an IC50 of 70 nM. However, its
development was hampered by the observation that two
major long-lived and active metabolites, the corresponding
sulfone and sulfoxide, were circulating in rats and monkeys.
This observation triggered the search for structurally distinct
5-LO inhibitors. All compounds prepared were evaluated for
their potency to inhibit the oxidation of arachidonic acid by
recombinant human 5-LO (H5-LO),14 and the production of
LTB4 in calcium ionophore-stimulated HWB.15 Each section
of the molecule was investigated, but the most interesting
modulation of structure-activity relationship (SAR) came
from replacement of the central mercaptobenzene moietyof
inhibitor 2. Most structural modifications of this moiety, even
subtle ones like replacing the sulfur atom by an oxygen atom
(3), were deleterious to potency and brought the HWB IC50
above 1 μM. The few analogues that retained submicromolar
potency are depicted in Table 1. Among them, thiazole 4
rapidly caught our attention since it retained high potency in
the H5-LO assay (IC50 = 20 nM) and showed only a 4-fold
L
cess.1 The synthesis of all LTs requires the action of the
enzyme 5-lipoxygenase2 (5-LO) and its accessory protein,
5-LO-activating protein3 (FLAP). Inhibition of 5-LO reduces
the production of both LTB4 and cysteinyl LTs (CysLTs) LTC4,
LTD4, and LTE4. CysLTs increase vascular permeability, con-
tract smooth muscle cells, and are involved in increased
mucus production. LTB4 is a potent chemoattractant for
neutrophils, macrophages, and other inflammatory cells
and induces chemokinesis and adhesion of these cells to
the vascular endothelium. Therefore, 5-LO inhibitors have
potential therapeutic utility for the treatment of inflamma-
tory disorders.4 Asthma, an inflammatory disorder of the
lower airway, is characterized by variable and reversible
bronchoconstriction, airway edema, mucus secretion, and
airway remodeling, which leads to recurrent episodes of
wheezing, breathlessness, chest tightness, and coughing.5
The clinical importance of the LTs in asthma has been well-
demonstrated both by drugs that inhibit the biosynthesis of
these mediators such as zileuton6 (1, Table 1; the only
marketed 5-LO inhibitor) and MK-05917 (a FLAP inhibitor)
and by potent CysLT1 receptor antagonists such as monte-
lukast.8 Theoretically, 5-LO inhibition could provide added
benefit over CysLT1 receptor antagonists by blocking LTB4-
mediated inflammation in addition to reducing CysLTs pro-
duction. LTs are also thought to play an important role in the
pathogenesis of chronic obstructive pulmonary disease
(COPD). COPD is characterized by an inflammatory process
in the airways dominated by neutrophils and effector T-cells.
LTB4 may be important in contributing to the inflammatory
process via both cell types and has been detected in both
the sputum and the lungs of patients with COPD. Cur-
rently available chronic medications for COPD have limited
Received Date: February 10, 2010
Accepted Date: March 27, 2010
Published on Web Date: April 13, 2010
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Table 1. SAR at the Central Ring Position
Table 2. SAR at the Tertiary Alcohol Position in the Thiazole Series
IC50 (nM)a
H5-LO
Ki (μM)a
compd
R1
R2
HWB
hERG
4
CF3
Me
Et
CF3
Me
Et
20 ( 16
1230 ( 480
23 ( 6
310 ( 160
520 ( 310
37 ( 20
1.2 ( 0.1
2.9 ( 0.1
2.1 ( 0.2
1.5 ( 0.1
0.9 ( 0.1
1.1 ( 0.1
9
10
11
CF3
CF3
CF3
CF3
CF3
Et
Me
Et
30 ( 4
150 ( 40
50 ( 18
12
14 ( 4
13
i-Pr
t-Bu
Et
12 ( 4
88 ( 12
14
18 ( 1
210 ( 40
83 ( 33
(S)-12
(R)-12
79 ( 15
7 ( 2
0.9 ( 0.1
1.3 ( 0.2
CF3
31 ( 22
a Each IC50 value corresponds to an average of at least two indepen-
dent determinations ((SD).
(Cmax) of 2.0 μM were observed, with an elimination half-life
(t1/2) of 4.3 h. The potency of (R)-12 on the ex vivo generation
of LTB4 in whole blood stimulated with calcium ionophore
A23187 was measured in a dog model.16 In vitro, thiazole
(R)-12 is 3-fold more potent in a dog whole blood assay (IC50
=
10 nM) than it is in the HWB assay (IC50 =31 nM). Following
oral dosing in dogs at a dose of 4 mg/kg, (R)-12 exhibited
>94% inhibition of LTB4 in dog whole blood ex vivo up to 24 h.
This level of inhibition is consistent with the potency of the
compound in the dog whole blood assay and the measured
plasma concentrations that are greater than 0.18 μM at all time
points, up to 24 h. The remarkable profile of this 5-LO inhibitor
triggered exploratory ancillary pharmacology studies. One of
these studies evaluated the effect of (R)-12 on the cardiovas-
cular system of anesthetized and vagotomized dogs, following
the administration of 4 mg/kg/h of the drug by i.v. infusion, for
2 h. Unfortunately, upon examination of the electrocardiograms,
a clear QTc interval prolongation was noted in treated dogs,
beginning 45 min after initiation of the infusion. The maximum
effect on mean QTc interval reached þ9% (as compared to
control) after 90 min of dosing, with an average plasma ex-
posure of 10 μM. Given a targeted trough exposure of 100 nM
for efficacy in the clinic, the likely therapeutic margin in
humans was estimated to be too low to warrant the clinical
development of (R)-12.
It is known that a variety of drugs that exhibit prolongation
of the QTc interval tend to block the voltage-gated potassium
channel encoded by the human ether-a-go-go gene (hERG).17
The affinity of molecules for this channel can be measured in
vitro by using a MK-499 displacement binding assay.18 5-LO
inhibitor (R)-12 exhibits a relatively high binding affinity in
this assay with a Ki of 1.3 μM (Table 2). Because of the
correlation between the prolongation of the QTc interval
observed with (R)-12 in vivo in dogs and the potency of
a Each IC50 value corresponds to an average of at least two indepen-
dent determinations ((SD). b Ref 19.
loss of activity in the HWB assay (IC50 = 310 nM) as com-
pared to inhibitor 2. Many analogues of thiazole 4 were
prepared, and it became clear that appropriate modification
of the substitution pattern at the tertiary alcohol provided a
major gain of potency in the HWB assay, as shown in Table 2.
Replacing the two trifluoromethyl groups of compound 4 by
two methyl groups brought a 2-fold loss of potency in the
HWB assay (compound 9). Conversely, substitution by two
ethyl groups was favorable, generating inhibitor 10 with an
IC50 of 37 nM. Highly potent inhibitors were also obtained
by an asymmetric substitution at the tertiary alcohol
(compounds 11-14, all racemic). The optimal potency in
this series was obtained by keeping one trifluoromethyl and
one ethyl group to generate racemic inhibitor 12 (HWB IC50
=
50 nM). Both enantiomers of 12 were prepared, and it was
observed that (R)-12, withanIC50 of 31 nM in the HWB assay, is
more potent than isomer (S)-12. The stereochemical assign-
ment was established by X-ray crystallography analysis.
In contrast to what was observed for inhibitor 2,13 thiazole
(R)-12 is orally bioavailable in rat, without having to rely on the
administration of a hydroxy acid prodrug. Thus, upon dosing
male rats with (R)-12 orally at 20 mg/kg in 0.5% methocel,
good bioavailability (F=37%) and a maximum concentration
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Table 3. SAR at the Tertiary Alcohol Position in the Oxadiazole
Series
Scheme 1a
IC50 (nM)a
Ki (μM)a
compd
R1
CF3 CF3
Et Et
R2
H5-LO
HWB
hERG
8
45 ( 10
130 ( 25
10 ( 3
690 ( 320
36 ( 17
52 ( 16
100 ( 30
52 ( 21
8.0 ( 0.2
14.5 ( 0.4
5.0 ( 0.8
7.7 ( 0.8
6.3 ( 0.7
15
16
CF3 Et
CF3 Et
(R)-16
230 ( 70
3.9 ( 2.1
(S)-16 (MK-0633) Et
CF3
a Each IC50 value corresponds to an average of at least two indepen-
dent determinations ((SD).
a Reagents and conditions: (a) NaH, 3,4-dimethoxybenzyl alcohol,
DMF, 83%. (b) n-BuLi, CF3COCF3, Et2O/THF, 59%. (c) HCO2NH4, Pd-C
10%, MeOH, Δ, 80%. (d) 2,2,6,6-Tetramethyl-3,5-heptanedione, CuCl,
Cs2CO3, NMP, 120 °C, 35%.
(R)-12 in the hERG binding assay, we have taken the binding
affinity for the hERG potassium channel as measured in the
MK-499 binding assay as an in vitro indicator for the poten-
tial for causing QTc interval prolongation. Therefore, our
efforts focused on identifying those portions of the molecule
that could be modified in such a way to decrease the affinity
for the hERG channel while maintaining or improving the
inhibitory potency against 5-LO. All of the thiazole deriva-
tives described in Table 2 show a similar affinity for the hERG
channel (Ki=0.9-2.9 μM). On the other hand, modification
of the central ring system seems to have a more profound
effect on hERG binding affinity, as shown in Table 1. In this
regard, oxadiazole derivative 8 is of particular interest with
a hERG binding Ki of 8.0 μM, representing a 6-fold loss
of affinity as compared to thiazole (R)-12. Unfortunately,
oxadiazole 8 also shows a considerable loss of potency in the
HWB assay (IC50=690 nM). By applying the lessons learned
in the thiazole series to the oxadiazole case, we were hopeful
that potency could be restored. The gem-diethyl derivative
15 was prepared and presented a potency equivalent to that
shown by inhibitor (R)-12 in the HWB assay (IC50 =36 nM),
accompanied by a significantly lower affinity for the hERG
channel (Ki=14.5 μM, Table 3). The pharmacokinetic profile
of this compound was not optimal though. Upon dosing
male rats intraveneously with 15, a short elimination half-life
of 1 h was observed. This problem was solved by preparing
the asymmetric alcohol 16, bearing a trifluoromethyl and an
ethyl group. Racemic inhibitor 16 presented good potency in
the HWB assay with an IC50 of 52 nM. Both enantiomers of
16 were prepared, and the stereochemical assignment was
again established by X-ray crystallography analysis. Enan-
tiomer (S)-16, with an IC50 of 3.9 nM in the H5-LO assay
and an IC50 of 52 nM in the HWB assay, is more potent than
isomer (R)-16. This excellent 5-LO inhibitory profile is acc-
ompanied by a relatively low affinity for the hERG channel
(Ki = 6.3 μM). Oxadiazole (S)-16 inhibits specifically 5-LO
and is not active against 12-LO, 15-LO, and FLAP (>20 μM).
The activity against FLAP was determined by measuring the
Scheme 2a
a Reagents and conditions: (a) LDA, R1COR2, THF, -78 °C. (b) LDA,
CF3CO2Et, THF, -78 to 0 °C, 68%. (c) RM, THF. (d) Compound 20, K2C3,
NMP, 120 °C.
displacement of a radiolabeled FLAP ligand from human
polymorphonuclear cell membranes. Oxadiazole (S)-16 pre-
sents a good pharmacokinetic profile in many preclinical
species (rat, 5 mg/kg iv, 20 mg/kg po, F = 66%, and t1/2
=
3.3 h; dog, 5 mg/kg iv, 4 mg/kg po, F=64%, and t1/2=5.3 h;
and rhesus monkey, 5 mg/kg iv, 4 mg/kg po, F = 54%, and
t1/2 = 3.6 h). In vitro, 5-LO inhibitor (S)-16 is 2-fold more
potent in a dog whole blood assay (IC50=21 nM) than it is in
the HWB assay (IC50=52 nM). Following oral dosing in dogs
at a dose of 2 mg/kg, (S)-16 exhibited >98% inhibition of
LTB4 in dog whole blood ex vivo up to 6 h. This level of
inhibition is consistent with its potency in dog whole blood
and the measured concentration of drug in the plasma that is
greater than 0.28 μM at all time points up to 6 h. Inhibition of
LTB4 at 24 h was ∼60%, although the drug concentration in
plasma was below the detection limit of 10 nM. Furthermore,
and in contrast to what was observed with thiazole (R)-12, the
oxadiazole inhibitor (S)-16 did not show adverse effects on the
cardiovascular system of anesthetized and vagotomized dogs.
Thus, following the administration of cumulative doses of 1, 3,
and 10 mg/kg of the drug by i.v. infusion (each dose infused
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Scheme 3a
Scheme 5a
a Reagents and conditions: (a) Chiral HPLC, Chiralpak AD column.
(b) Compound 20, K2CO3, NMP, 120 °C.
Scheme 4a
a Reagents and conditions: (a) EtMgBr, Et2O, -78 °C, 76%; (b) NaOH,
THF/MeOH, 90%; (c) (S )-(+)-2-phenylglycinol, HATU, DIPEA, DMF,
41%; (d) H2SO4, dioxane, 105 °C; (e) CH2N2, Et2O, 74% (2 steps); (f)
H2NNH2, 120 °C; (g) BrCN, CHCO3, H2O, 71% (2 steps); (h) 25, toluene,
Δ; (i) NaBH4, EtOH 54% (2 steps).
enantiomer was subsequently reacted with bromide 20
to afford inhibitors (S)-12 and (R)-12. The preparation
of analogues 5, 6, and 7 is described in the Supporting
Information. The preparation of 2-amino-oxadiazole deriva-
tives 8, 15, and 16, described in Scheme 4, involved the
synthesis of key intermediates 31a-c. Reaction of ester 30
[obtained by treatment of 2,2-bis(trifluoromethyl)-2-hydro-
xyacetic acid with diazomethane], first with hydrazine and
then with cyanogen bromide, gave access to oxadiazole 31a.
Alternatively, a similar sequence was applied to diethylox-
alate and was followed by the addition of excess ethylmag-
nesium bromide to produce analogue 31b. As for asymmetric
derivative 31c, its synthesis involved addition of ethylmag-
nesium bromide to ethyl trifluoropyruvate and subsequent
reaction with hydrazine and with cyanogen bromide.
The desired final products were then obtained by reductive
amination reactions between the appropriate amines 31 and
aldehyde 25 (see Supporting Information). The two enantio-
mers of inhibitor 16 were first obtained by submitting the
racemic mixture to a chiral separation on a Chiralpak AD
column. Afterward, larger quantities of the most active
enantiomer (S)-16 were produced by following the synthetic
route depicted in Scheme 5. Addition of ethylmagnesium
bromide to ethyl trifluoropyruvate was followed by hydrolysis
of the resulting hydroxy-ester to afford racemic acid 32.
Coupling with (S)-2-phenylglycinol afforded a diastereomeric
mixture that was purified by flash chromatography on silica gel
to deliver diastereomerically pure amide (S,S)-33. Hydrolysis
of the amide bond followed by esterification produced methyl
ester (S)-34. The usual treatment with hydrazine and with
cyanogen bromide gave oxadiazole (S)-35, and reductive
amination with aldehyde 25 completed the preparation of
multigram quantities of potent 5-LO inhibitor (S)-16.
a Reagents and conditions: (a) H2NNH2, Δ; (b) BrCN, KHCO3, H2O; (c)
EtMgBr; (d) 25, toluene, Δ; (e) NaBH4, EtOH.
over 30 min), no treatment-related changes in the PR, QRS,
and QTc intervals were observed, with an average plasma
exposure of 9, 14, and 49 μMatthosethreedoses, respectively.
The 5-LO inhibitors described in this study were prepared
as shown in Schemes 1-5. The synthesis of diaryl ether 3
started by the addition of 3,4-dimethoxybenzyl alcoholate to
1-bromo-3,5-difluorobenzene (Scheme 1) to provide benzyl
ether 17. Bromine-lithium exchange followed by treatment
with hexafluoroacetone gave access to tertiary alcohol 18,
which after deprotection afforded phenol 19. The desired
diaryl ether 3 was finally obtained by engaging intermediate
19 with the known aryl bromide 2013 under Ullmann ether
synthesis conditions. The 2-thiazolyl thioethers 4 and 9-14
were prepared by two different pathways (Scheme 2).
Deprotonation of 2-mercaptothiazole with lithium diisopro-
pyl amide (LDA), followed by addition of hexafluoroacetone,
acetone, 3-pentanone, or 1,1,1-trifluoro-2-butanone, gave
tertiary alcohols 21a, b, c, and e, respectively. Alternatively,
deprotonation of 2-mercaptothiazole with LDA followed by
addition of ethyl trifluoroacetate gave ketone 22. Addition of
methylmagnesium bromide, isopropylmagnesium chloride,
or tert-butyllithium to 22 yielded alcohols 21d, f, and g,
respectively. The desired thioethers were obtained by heat-
ing the appropriate 2-mercaptothiazoles 21 with bromocou-
marin 20 in 1-methyl-2-pyrrolidinone (NMP). The two
enantiomers of inhibitor 12 were obtained by submitting
the racemic mixture of asymmetric alcohol 21e to a chiral
separation on a Chiralpak AD column (Scheme 3). Each
In summary, we have discovered a series of novel 5-LO
inhibitors that are potent, selective, and orally bioavailable.
A major focus of the optimization effort was to preserve the
5-LO inhibitory potency while reducing the affinity for the
hERG potassium channel. This work culminated in the identi-
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fication of 4-(4-fluorophenyl)-7-[({5-[(2S)-1,1,1-trifluoro-
2-hydroxybutan-2-yl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-
chromen-2-one [(S)-16, MK-0633, setileuton]. On the basis
of its overall profile, setileuton was selected for clinical deve-
lopment, and its effect on the treatment of asthma and
COPD will be reported in separate papers.
Guay, J.; Hamel, P.; Riendeau, D.; Soucy-Breau, C.; Tagari, P.;
Girard, Y. Substituted coumarins as potent 5-lipoxygenase
inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 2528–2531.
(14) The protocol to perform the H5-LO assay is described in the
Supporting Information.
(15) Brideau, C.; Chan, C.; Charlson, S.; Denis, D.; Evans, J. F.;
Ford-Hutchinson, A. W.; Fortin, R.; Gillard, J. W.; Guay, J.;
ꢀ
Guevremont, D.; Hutchinson, J. H.; Jones, T. R.; Leger, S.;
SUPPORTING INFORMATION AVAILABLE Experimental
synthetic procedures, spectroscopic characterization, and H5-LO
assay protocol. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
Mancini, J. A.; McFarlane, C. S.; Pickett, C.; Piechuta, H.;
Prasit, P.; Riendeau, D.; Rouzer, C. A.; Tagari, P.; Vickers, P. J.;
Young, R. N.; Abraham, W. M. Pharmacology of MK-0591
(3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-
indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally
active leukotriene biosynthesis inhibitor. Can. J. Physiol.
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AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. E-mail: yves_ducharme@merck.com.
(16) Tagari, P.; Becker, A.; Brideau, C.; Frenette, R.; Sadl, V.;
Thomas, E.; Vickers, P.; Ford-Hutchinson, A. Leukotriene
generation and metabolism in dogs: Inhibition of biosynthe-
sis by MK-0591. J. Pharmacol. Exp. Ther. 1993, 265, 416–25.
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ACKNOWLEDGMENT We acknowledge the contribution of
Nancy N. Tsou (Merck Research Laboratory, Rahway) for the
structure determination of compounds (R)-12 and (S,S)-33 by
X-ray diffraction.
(18) Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.;
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