Wake-promoting agents: Search for next generation modafinil: Part i

Article abstract of DOI:10.1016/j.bmcl.2011.12.099

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.

Full text of DOI:10.1016/j.bmcl.2011.12.099

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2312–2314
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Wake-promoting agents: Search for next generation modafinil: Part I
Derek Dunn, Greg Hostetler, Mohamed Iqbal, Patricia Messina-McLaughlin, Alyssa Reiboldt,
⇑
Yin Guo Lin, John Gruner, Edward R. Bacon, Mark A. Ator, Sankar Chatterjee
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phe-
nyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has
been selected for additional studies.
Received 18 November 2011
Accepted 20 December 2011
Available online 29 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Wake-promoting agents
Modafinil
Bi-phenyl
While modafinil continues to be evaluated in a variety of ex-
panded clinical applications, a few aspects of its overall profile
have served as the cornerstone for efforts to identify a follow-on
molecule. Modafinil demonstrates modest inhibition of CYP 2C19
O
S
O
(IC50 = 11
and CYP 2D6. Since clinical studies demonstrated that human plas-
ma concentrations can reach levels greater than 30 M at effica-
lM) but shows virtually no interaction with CYP 3A4
NH2
l
cious dose, the potential for drug–drug interactions is possible
which will become important as modafinil is used as an adjunctive
therapy in many patients with psychiatric and/or neurological dis-
orders. In addition, it was anticipated that a follow-on molecule
from a different chemical class with modafinil-like (or better) pro-
file, distinct from classical psychostimulants, might shed more
light in elucidating the mechanism of action of modafinil and wake
promoting mechanisms in general, especially contributory roles
played by various transporters.
Cl
17
Disorders of ‘wakefulness’, including states of impaired alert-
ness, vigilance and attention affect millions of individuals. Rela-
tively few pharmacotherapies are available to treat such
symptoms. Stimulants (caffeine, amphetamine and methylpheni-
date) are among the main pharmacological interventions that can
improve or enhance waking but suffer from various limiting side ef-
fects. Modafinil (compound 1, Fig. 1), a novel agent, pharmacologi-
cally distinct from classical stimulants, improves wakefulness in a
variety of species and is efficacious in humans with few peripheral
or central side effects.1 While the precise mode of action of modafi-
nil has yet to be well-defined, mechanistic studies frequently have
centered on the involvement of dopamine transporter (DAT) and
norepinephrine transporter (NET) as either causal or indirect con-
tributors to modafinil’s wake promoting pharmacology.2–4
Scheme 1 depicts the general synthetic scheme that was uti-
lized to generate the target compounds. Coupling of compounds
2 and 3 in acidic media generated compound 4 that on basic hydro-
O
S
O
O
S
O
NH2
NH2
X
A
1
Figure 1. Chemical structures of modafinil and new generation of wake-promoting
agents.
⇑
Corresponding author.
E-mail address: Sankar.Chatterjee24@gmail.com (S. Chatterjee).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.099

D. Dunn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2312–2314
2313
O
b
S
a
S
OH
+
S
NH2
NH
X
NH2
H2N
I
I
I
X = OH
X = NH2
5
c
4
2
3
6
d
O
S
O
e
B(OH)2
O
S
O
NH2
X
+
NH2
I
X
9 - 27
7
8
Scheme 1. Reagents and conditions: (a) 48% HBr, H2O, mixing at 60 °C followed 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, reflux, 3 h; (ii) 28% NH4OH, CH2Cl2, 0 °C to rt 0.5 h 70% over two steps; (d) 50% H2O2, gl. acetic acid, rt, 2 h, 90%; (e) Tetrakis (triphenylphosphine)Pd,
2 M Na2CO3, EtOH–toluene, 80 °C, 1–3 h, 60–80%.
Table 1
lysis followed by treatment with chloroacetic acid generated car-
boxylic acid 5 that in turn was converted to amide 6. Controlled
Structure–activity relationship of new analogs
oxidation of compound 6 generated corresponding racemic sulfinyl
compound 7. Suzuki coupling between compound 7 and various
commercially available boronic acids 8 yielded target compounds
9–27.
p
O
S
O
A
2
m
NH2
X
o
1
B
At the outset of our synthetic program, no well-defined molec-
ular target(s)4b,c and no historical database of modafinil’s wake
promotion structure–activity relationships existed in the litera-
ture.5 Thus the members of the new series were initially evaluated
for their brain permeability in rat PK studies (data not shown).
Subsequently, their cumulative wake-promoting activity in rat
(i.e., total time (minutes) awake over a period of 3 h after dosing
(3 h AUC) at 100 mg/kg ip) compared to modafinil was utilized as
the principal parameter in generating an in vivo SAR correlation
(Table 1).6
4
3
9 - 27
Compound
Orientation of phenyl
rings
X
Rat wake 3 h AUC minutesa
1 (modafinil) —
9
—
H
2-F
117 13*
119 14*
64
86 13
49 10.6
99 20
o-
o-
o-
o-
o-
o-
o-
o-
o-
o-
o-
o-
o-
o-
m-
m-
m-
p-
p-
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Vehiclec
2-OMe
2-Cl
3-CN
As mentioned previously, at the outset of our synthetic pro-
gram, no known molecular target describing modafinil-SAR ex-
isted in literature. Thus exploration began with the
rearrangement of two phenyl rings of the parent molecule main-
taining the sufinylacetamide moiety, thought to be unique for a
CNS drug, intact. Thus, a series of bi-phenyls (ortho-, meta- and
para-orientations) were generated (structure A, Fig. 1). As shown
in Table 1, in ortho-series the parent compound 9 displayed
equal activity to compound 1 while substitution at the 2-posi-
tion of ring B diminished wake-promoting activity (cf. compound
1 vs compounds 10, 11 and 12). On the other hand, while a cy-
ano group and a carboxamide group at position-3 of ring B
(compounds 13 and 14) were detrimental, chlorine at the same
position was beneficial (cf. compound 15 vs compound 12). Sub-
stitution at 4-position of ring B with halogens (compounds 16,
17 and 18), methyl (compound 19) and trifluoromethoxy (com-
pound 20) were tolerated but an acetyl group (compound 21)
and a cyano group (compound 22) were not tolerated. Effect of
meta- and para-orientations of two phenyl groups were explored
in compounds 23–27, but without any additional advantage. Two
SAR trends in Table 1 are worth noting. In ortho-bi-phenyl series,
a chlorine dance in ring B, going from position 2 (compound 12)
to position 3 (compound 15) to position 4 (compound 17) made
a significant improvement in activity. On the other hand, main-
taining the 4-chloro substitution fixed in ring B, the orientation
3-CONH2 62
8
3-Cl
4-F
106 14*
147 11*
176 4*
174 4*
146 2*
108 22
4-Cl
4-Br
4-Me
4-OCF3
4-COMe
4-CN
H
2-Me
4-Cl
H
77
65
5
8
NTb
117 11*
96 11*
100
92 17
65
6
4-Cl
—
9
a
b
c
Mean SEM.
Not tested.
Average of vehicle group: mean and SEM values (N = 11) for compounds shown.
P <0.05 versus within-experiment vehicle.
*
of two phenyl rings going from ortho- (compound 17) to meta-
(compound 25) to para-(compound 27) had a detrimental effect
on activity.
Based on its superior activity versus modafinil in the rat wake
promotion assay, compound 17 was selected for further profiling.
Table 2 displays a selected set of data for both compounds. While

2314
D. Dunn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2312–2314
Table 2
References and notes
Selected comparative profile of compound 17 versus compound 1
1. Modafinil is marketed by Cephalon, Inc., Frazer, PA under the trade name
ProvigilÒ. Detailed information on the drug could be found in the website http://
www.provigil.com (accessed on November 10, 2011).
2. Andersen, M. L.; Kessler, E.; Murnane, K. S.; McClung, J. C.; Tufik, S.; Howell, L. L.
Psychopharmacology 2010, 210, 439.
3. Volkow, N. D.; Fowler, J. S.; Logan, J.; Alexoff, D.; Zhu, W.; Telang, F.; Wang, G. J.;
Jayne, M.; Hooker, J. M.; Wong, C.; Hubbard, B.; Carter, P.; Warner, D.; King, P.;
Shea, C.; Xu, Y.; Muench, L.; Apelskog-Torres, K. JAMA 2009, 301, 1148.
4. (a) Madras, B. K.; Xie, Z.; Lin, Z.; Jassen, A.; Panas, H.; Lynch, L.; Johnson, R.; Livni,
E.; Spencer, T. J.; Bonab, A. A.; Miller, G. M.; Fischman, A. J. J. Pharmacol. Exp. Ther.
2006, 319, 561; (b) Nishino, S.; Mao, S.; Sampathkumaran, R.; Shelton, J. Sleep
Res. Online 1998, 1, 49; (c) Mignot, E.; Nishino, S.; Guilleminault, C.; Demont, W.
C. Sleep 1994, 17, 436.
Assay
1
17
Solubility:
l
g/mL at pH 7.4
>100
77
3.7/4.3
63.9/>300
<10%
>100
94
0.6/0.83
10/>300
<10%
19
Clean
Clean
Active
Human S9 metabolism (% parent remaining at 2 h)
DAT binding/DAT uptake inhibition (rat IC50 M)
NET/SERT uptake inhibition (rat IC50 M)
CYP 3A4/2D6 inhibition at 10
CYP 2C19 inhibition (IC50
Mini-Ames
l
l
l
M)
M
l
11
Clean
Not tested
Active
hERG (% inhibition at 10
Wake promotion in rat (100 mg/kg, ip)
lM)
5. After our work was completed, following publication describing several
modafinil analogs appeared in the literature: Cao, J.; Prisinzano, T. E.;
Okunola, O. M.; Kopajtic, T.; Shook, M.; Katz, J. L.; Newman, A. M. ACS Med.
Chem. Lett. 2010, 2, 48.
both displays acceptable level of water solubility, compound 17
was metabolically more stable than compound 1 in a human liver
S9 metabolism assay. Compound 17 appeared to be more potent
than compound 1 both in DAT binding and DAT reuptake inhibition
assays (rat). However, it is not known how this will translate in hu-
man. While both compounds displayed low activity in SERT uptake
inhibition assay, compound 17 was slightly more potent in the NET
uptake inhibition assay. While both compounds did not display lia-
bility in CYP 3A4 and 2D6 assays, compound 17 was ca. twofold
less potent in 2C19 assay. Compound 17 did not display any liabil-
ity either in mini-Ames or hERG inhibition assay. In rat wake pro-
motion assay, compound 17 also displayed potency via oral route
(data not shown). Accordingly, compound 17 was selected for
additional in vivo behavioral profiling and was also selected for
separation into its corresponding enantiomers and profiling of each
isomer individually.
6. Experimental protocol for wake promotion study. Adult, male Sprague Dawley rats
were used. Room lights were on from 7 AM to 7 PM. Test compounds were
administered in 0.5% methylcellulose/0.2% tween-80 in distilled water, pH 6.2 at
5 ml/kg IP. Sleep/wake data was recorded and scored according to methods
described by Edgar and Seidel,7 Opp and Krueger,8 and Scammell et al.9 Cortical
EEG and neck EMG activity were recorded differentially using screw electrodes
over the frontal cortex (+3.0 mm AP from bregma, 2.0 mm mediolateral) and
hippocampus (À4.0 mm AP from bregma, 2.5 mm mediolateral). Electrodes
were chronically implanted in rats under Nembutal anesthesia. The day before
recording, rats were placed in individual containers (31 Â 31 Â 31 cm) in sound-
attenuating cabinets and connected by cables to the recording equipment. Food
and water were available ad libitum. Each cabinet contained a fan, a light (12 h
light/12 h dark cycle), and a speaker to provide background noise. EEG and EMG
signals were amplified (10 and 1 K, respectively) and band pass filtered between
0.3 and 500 Hz for EEG and between 10 and 500 Hz for EMG. These signals were
digitized at 128 samples per second using ICELUS sleep scoring software (M.
Opp). Animals were dosed at 1 PM (5 h after lights on, CT-5) by IP injection,
which produces a brief awakening.
Data Analysis. Approximately 30–60 min of EEG/EMG data prior to dosing was
scored manually into wake, slow-wave sleep (SWS), and REM sleep (REMS)
stages using 6 s epochs based on published criteria. The remainder of the data
was scored with an autoscoring algorithm utilizing parameters optimized to
match manually scored data. The primary outcome measures were cumulative
time awake for 3 h after dosing (3 h AUC).
Statistical analysis. Values are listed as mean of data from at least three animals.
Treatment effects were evaluated using ANOVA. Treatment group comparisons
were made using unpaired, two-tailed t-tests or Dunnett’s t-test for multiple
comparisons as appropriate. Statistical comparisons were made against vehicle-
treated animals in the same experiment.
In this Letter, we disclosed a series of bi-phenyl derived wake-
fulness promoting agents (in rat) in search of a next generation
molecule to modafinil. From this work racemate compound 17
emerged as a lead molecule. This compound was selected for chiral
separation into corresponding enantiomers to profile each isomer
individually. Outcome of that research will be the subject of a fu-
ture publication.
Acknowledgment
7. Edgar, D. M.; Seidel, W. F. J. Pharmacol. Exp. Ther. 1997, 283, 757.
8. Opp, M. R.; Krueger, J. M. Am. J. Physiol. 1994, 266, R688.
9. Scammell, T. E.; Estabrooke, I. V.; McCarthy, M. T. J. Neurosci. 2000, 20, 8620.
Authors wish to acknowledge the scientific support and encour-
agement of Drs. Donna Bozyczko-Coyne, John P. Mallamo and Jeffry
L. Vaught during the course of this research.