Aryl-Heteroaryl Derivatives as Novel Wake-Promoting Agents

Article abstract of DOI:10.1111/cbdd.12083

In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.

Full text of DOI:10.1111/cbdd.12083

Chem Biol Drug Des 2013; 81: 429–432
Research Letter
Aryl-Heteroaryl Derivatives as Novel Wake-Promoting
Agents
Brigitte Lesur1, Yin G. Lin2, Val R. Marcy2, Lisa D.
Aimone2, John Gruner2, Edward R. Bacon2 and
Sankar Chatterjee2,*
1Cephalon (France), 19 Avenue du Professeur
Cadiot94700 Maisons-Alfort, Paris, France
2Cephalon, Inc., 145 Brandywine Parkway, West Chester,
PA 19380-4245, USA
*Corresponding author: Sankar Chatterjee,
sankar.chatterjee24@gmail.com
In search of a next generation molecule to the novel
wake-promoting agent modafinil, a series of aryl-hetero-
ayl-derived wakefulness enhancing agents (in rats) was
developed. From this work, compound 16 was sepa-
Figure 1: Structures of compounds 1, 2, and current series of
rated into its enantiomers to profile them individually.
wake-promoting agents A.
Key words: aryl, heteroaryl, modafinil, transporters, wake-
promoting agents
contributors to modafinil’s wake-promoting pharmacology
(1–4). While modafinil continues to be evaluated in a vari-
ety of expanded clinical applications, a few aspects of its
overall profile have served as the cornerstone for efforts to
identify a follow-on molecule. Modafinil demonstrates mod-
est inhibition of CYP2C19 (IC50 = 11 lM) but shows virtu-
ally no interaction with CYP3A4 and CYP2D6. As clinical
studies demonstrated that human plasma concentrations
can reach levels >30 lM at efficacious dose, the potential
for drug–drug interactions becomes important as modafinil
is used as an adjunctive therapy in patients with psychiat-
ric and ⁄ or neurological disorders. In addition, it was antici-
pated that a follow-on molecule from a different structural
scaffold with modafinil-like (or better) profile, distinct from
Received 17 August 2012, revised 18 September 2012 and
accepted for publication 16 October 2012
Modafinil (compound 1, Figure 1), a novel agent, pharma-
cologically distinct from classical stimulants (caffeine,
amphetamine, and methylphenidate), improves wakeful-
ness in a variety of species and is efficacious in humans
with few peripheral or central side effects.a While the pre-
cise mode of action of modafinil has yet to be well defined,
mechanistic studies frequently have centered on the
involvement of dopamine transporter (DAT) as well as nor-
epinephrine transporter (NET) as either causal or indirect
Scheme 1: Reagents and conditions:
(a) 48% HBr, H2O, mixing at 60 ꢀC fol-
lowed by reflux, 0.5 h, 90%; (b) (i) 10 N
NaOH, 80 ꢀC, 1 h; (ii) ClCH2COOH,
reflux, 2 h, 80% over two steps; (c) (i)
SOCl2, C6H6, heat, 3 h; (ii) 28%
NH4OH, CH2Cl2, 0 ꢀC to room temp.,
0.5 h 70% over two steps; (d) 30%
H2O2, gl. acetic acid, room temp., 2h,
90%; (e) Pd(PPh3)4, 2 M Na2CO3, EtOH
– toluene, 80 ꢀC, 1–3 h, 55–75%; (f)
HPLC-separation utilizing chiralpak AS
column eluting with CH3CN.
ª 2012 John Wiley & Sons A/S. doi: 10.1111/cbdd.12083
429

Lesur et al.
Table 1: Biological data of novel and reference compounds
classical psychostimulants, might shed more light in eluci-
dating the mechanism of action of modafinil and wake-
promoting mechanisms in general, especially contributory
roles played by various transporters. Recently, our labora-
tories disclosed biphenyl-derived racemic compound 2
(Figure 1) as a novel wake-promoting agent (5); subse-
quently, the group also disclosed profiles of enantiomers
of compound 2 from ongoing studies (6). In parallel to the
above-mentioned research, our laboratories also explored
a series of phenyl-heteroaryl and phenyl-cycloalkene deriv-
atives, exemplified by generic structure A (Figure 1). In this
Letter, a preliminary report of this effort is disclosed.
p
O
S
O
Heteroaryl
A
/ cycloalkene
NH2
m
o
10 - 20
10–20
Confign.
of rings
Heteroaryl ⁄
cycloalkene
Rat wake 3 h
AUC (mina)
Compound
1
2
10
–
–
–
–
117 13*
176 4*
61 11
Ortho
Scheme 1 depicts the general synthetic scheme that was
utilized to generate several target compounds. Coupling of
commercially available compounds 3 and 4 in acidic
media generated compound 5 that on basic hydrolysis fol-
lowed by treatment with chloroacetic acid generated car-
boxylic acid 6. Compound 6 was converted to amide 7 via
the intermediacy of corresponding acid chloride. Con-
trolled oxidation of compound 7 generated corresponding
racemic sulfinyl compound 8. Suzuki coupling between
compound 8 and various commercially available boronic
acids 9 yielded target compounds 10–20 (7). One of the
target compounds, racemate 16, was subsequently sepa-
rated into corresponding enantiomers ())-16 and (+)-16;
the former being the first eluant (absolute configuration of
either enantiomer is currently unknown).
O
2
11
12
13
14
Ortho
Ortho
Ortho
Ortho
77
53
8
7
S
1
3
2
S
1
3
114 3**
125 8***
N
1
2
2
5
Cl
S
1
At the outset of our synthetic program, no well-defined
molecular target(s) nor did any historical data regarding
modafinil’s wake promotion structure-activity relationship
(modafinil – SAR) exist in the literature (3). Thus, the mem-
bers of the new series were initially evaluated for their
brain permeability in rat pharmacokinetic (PK) studies.
Subsequently, following our previously published experi-
mental protocol (5) cumulative wake-promoting activity in
rats [i.e., total time in minutes awake over a period of 3 h
after dosing (3 h AUC) at 100 mg ⁄ kg i.p.] compared with
modafinil was utilized as the principal parameter in gener-
ating an in vivo SAR correlation. Table 1 displays the bio-
logical data for a subset of compounds from the series as
well as data for reference compound 1 and previously dis-
closed compound 2.
3
15
16
17
18
19
Ortho
Ortho
Meta
150 13*
172 3***
109 14
90 25
2
S
1
2
S
1
2
S
1
Ortho
Ortho
64 10
20
Vehicleb
Ortho
–
66
67
7
3
–
In the previously disclosed compound 2 (Figure 1), two
phenyl rings (A and B) were directly attached to each other
(5). In the current series, while keeping ring A containing
the sulfinylacetamide moiety fixed, ring B was substituted
with either a heteroaryl or a cycloalkene moiety. However,
taking a hint from the first series, a major effort was
expended in generating several ortho analogs. As shown
in Table 1, initial analogs 10 (2-furanyl derivative), 11 (2-thi-
ophenyl derivative), and 12 (3-thiophenyl derivative), each
containing a five-member aromatic heterocycle, were not
as active as the reference compound 1 in the rat wake
promotion assay. However, inclusion of a 3-pyridyl moiety
(compound 13) maintained the activity of compound 1. On
aMean SEM; *p < 0.05, **p < 0.01, ***p < 0.001, versus within
experiment vehicle.
bMean SEM of nine vehicle means for compounds 10–20
above.
the other hand, introduction of a 5-chloro substitution in
compound 11 generated compound 14 that also main-
tained the activity of reference compound 1. It appeared
additional steric bulk in heteroaryl ring B might be benefi-
cial. This proved to be the case when the 3-thienyl group
was fused with a phenyl ring as in compound 15 that was
430
Chem Biol Drug Des 2013; 81: 429–432

Novel Wake-Promoting Agents
Table 2: Biological data for compounds 1, ())-16, (+)-16, ())-2 and (+)-2
Assay
1a
())-16
(+)-16
())-2b
(+)-2b
Vehicle
DAT binding (rat IC50 lM)
NET binding (rat Ki lM or % inhibition) NA
SERT binding (rat Ki lM or % inhibition) NA
3.70
0.0216
10
0.037
13
5.5
0.40
4.20
–
–
–
–
–
–
16% at 10 lM 12% at 10 lM
3% at 10 lM 4% at 10 lM
39% at 30 lM
29% at 100 lM 42% at 100 lM 174
CYP2C19 (IC50 lM or % inhibition)
CYP3A4 (IC50 lM or % inhibition)
CYP2D6 (IC50 lM or % inhibition)
Rat wake 4 h AUC
11
112
159
151
<10% at 10 lM <10% at 100 lM <10% at 100 lM 139
<10% at 10 lM 16% at 100 lM <10% at 100 lM 177
117 13*
175.7 2.9**
157.2 12.8**
238.5 0.8* 227.1 7.8* 67.8 4.5d
(100 mg ⁄ kg, i.p., minc)
aSee Note ’a’.
bReference (6).
cMean SEM; *p < 0.05, **p < 0.001 versus vehicle, unpaired t-test.
dAverage of vehicle group: N = 3–4 per group.
pound 1. Interestingly, they displayed comparatively similar
activity to each other, differentiating this pair from the pre-
viously disclosed enantiomers of compound 2 [6]. In a sim-
ilar way, in NET-binding assay (rat), current pair of
enantiomers displayed similar moderate activity (Ki of 10–
13 lM), while previously, disclosed pair ())-2 and (+)-2
were comparatively less active. In SERT-binding assay
(rat), enantiomer (+)-16 displayed moderate activity differ-
entiating this isomer from ())-16 as well as previously dis-
closed pair ())-2 and (+)-2.
CYP450 enzyme inhibitory data (Table 2) indicate that both
enantiomers exhibit better CYP2C19 profile than com-
pound 1 as well as extremely low levels of activity against
CYP3A4 and CYP2D6 isoforms, respectively, indicating
drug–drug interactions in a clinical setting might not be a
potential issue for the pair.
Figure 2: Brain levels of ())-16 and (+)-16 in pharmacokinetic
studies in rats (i.p., 100 mg ⁄ kg, vehicle: 0.5% methylcellulose,
0.2% tween 80).
more active than the reference compound 1. The activity
was improved in regioisomeric compound 16. On the
other hand, regioisomeric compound 17 with meta orien-
tation between the aryl and heteroaryl rings was less active
than compound 16 with ortho orientation between the
rings, reminiscent of the observation seen previously in
biphenyl series. Replacement of the aryl ring B in com-
pound 2 (Figure 1) with a series of cycloalkene rings (size
5–7) generated compounds 18, 19, and 20, respectively.
However, as shown in Table 1, this maneuver was not
productive indicating a fully aromatic system is preferred in
this class of wake-promoting agents (rats).
In rat PK studies (i.p., 100 mg ⁄ kg), the brain level expo-
sures of compounds ())-16 and (+)-16 were comparable
especially during the early time points (Figure 2). At the
1-h time point (Cmax), the brain concentration for ())-16
was 9350 509 ng ⁄ g versus 8650 703 ng ⁄ g for (+)-16.
The brain to plasma ratio for both compounds was also
consistent across all time points, 0.53 0.04 for ())-16
and 0.47 0.04 for (+)-16.
Finally, in the rat wake promotion assay, both ())-16 and
(+)-16 displayed superior activity compared with com-
pound 1 (Table 2). However, note that the duration of their
wake promotion activities was comparatively lower than
those of compounds ())-2 and (+)-2, respectively. Both
())-16 and (+)-16 are currently being profiled in various
behavioral paradigms.
Based on its superior activity versus compound 1 in the
rat wake promotion assay, representative compound 16
was selected for separation into corresponding enantio-
mers ())-16 and (+)-16 to investigate their individual profile.
Table 2 displays a set of preliminary data for the enantio-
mers along with similar data for the reference compound 1
and previously disclosed enantiomers ())-2 and (+)-2.
In this Letter, we disclosed a series of aryl-heteroayl-
derived wakefulness enhancing agents (in rats). From this
work, racemic compound 16 was separated into enantio-
mers to compare their profiles to that of reference com-
pound 1 as well as enantiomers of previously disclosed
novel compound 2.
In DAT-binding assay (rat), both enantiomers ())-16 and
(+)-16 displayed superior activity compared with com-
Chem Biol Drug Des 2013; 81: 429–432
431

Lesur et al.
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Acknowledgments
Authors wish to acknowledge the scientific support pro-
vided by Philippe Louvet, Dominique Schweizer, Marie-
Edith Gourdel, Eric Riguet and Christoph Yue and encour-
agement of Drs. Donna Bozyczko-Coyne, Mark A. Ator,
John P. Mallamo and Jeffry L. Vaught during the course of
this research.
Conflict of interest
6. Dunn D., Hostetler G., Iqbal M., Messina-McLaughlin
P., Reiboldt A., Lin Y.G., Gruner J., Bacon E.R., Ator
M.A., Chatterjee S. (2012) Wake-promoting agents:
search for next generation modafinil: Part II. Bioorg
Med Chem Lett;22:2315–2317.
7. Lesur B., Louvet P., Tripathy R. (2011) Thio-substituted
arylmethanesulfinyl derivatives. US Patent 8,071,604:
1–51.
All the authors were employees of Cephalon, Inc. that
markets modafinil.
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Chem Biol Drug Des 2013; 81: 429–432