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

Article abstract of DOI:10.1016/j.bmcl.2012.01.064

In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.

Full text of DOI:10.1016/j.bmcl.2012.01.064

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2315–2317
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 II
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:
Available online 28 January 2012
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously dis-
closed bi-phenyl derived racemate compound ( )-2 as a new generation of wake-promoting agent. Here
we describe the profiles of the individual enantiomers (ꢀ)-2 and (+)-2, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Wake-promoting agent
Modafinil
Transporters
Disorders of ‘wakefulness’ or vigilance affect millions of individ-
uals. 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 periph-
eral or central side effects.1 While the precise mode of action of
modafinil has yet to be defined, mechanistic studies frequently
have centered on the involvement of the dopamine transporter
(DAT) as well as the norepinephrine (NET) and serotonin (SERT)
transporters as either causal or indirect contributors to modafinil’s
wake promoting pharmacology.2–4 Recently, we disclosed bi-
phenyl derived racemate compound 2 as a new generation of
wake-promoting agent (Fig. 1).5 Subsequently, the research team
separated the enantiomers of compound 2 to profile them individ-
ually. Herein we disclose some preliminary results from our ongo-
ing investigation.
Scheme 1 depicts the synthetic scheme that was utilized to gen-
erate compound 2. Coupling of commercially available compounds
3 and 4 in acidic media generated compound 5 that, on basic
hydrolysis followed by treatment with chloroacetic acid, generated
carboxylic acid 6 that in turn was converted to amide 7. Controlled
oxidation of compound 7 generated corresponding racemic sulfinyl
compound 8. Suzuki coupling between compound 8 and commer-
cially available boronic acid 9 yielded target racemic compound 2
that was separated by chiral HPLC to generate individual enantio-
mers (ꢀ)-2 (eluting as the first peak) and (+)-2 (eluting as the sec-
ond peak).6,7
enantiomer was profiled in both transporter binding and uptake
inhibition assays. Results are shown in Table 1.
In parallel, both compounds were profiled in various CYP450
isoform inhibition assays to get a sense of their potential liability
issues in a clinical setting. Results are shown in Table 2.
In order to investigate their wake promotion activity in a rodent
species, both enantiomers were evaluated for their brain perme-
ability in rat PK studies (data not shown). Subsequently cumulative
wake-promoting activity in rat [i.e., total time (minutes) awake
over a period of 4 h after dosing (4 h AUC) at 100 mg/kg ip] was
determined (Table 3) following previously disclosed procedure.5
As shown in Table 1, the enantiomers behave differently both in
the DAT binding and uptake inhibition assays (rat) indicating the
role chirality plays in this class of molecules for binding to this
transporter. While both enantiomers displayed some level of activ-
ity in NET uptake inhibition assay, they lacked activity in SERT up-
take inhibition assay. Currently, the relative contribution of DAT
and NET in the biological activity of these molecules is not known
(vide infra).
O
S
O
O
S
O
NH2
NH2
Due to the implication of involvement of various transporters in
the mechanism of action of modafinil in recent literature, each
1
2
Cl
⇑
Corresponding author.
E-mail address: Sankar.Chatterjee24@gmail.com (S. Chatterjee).
Figure 1. Evolution of compound 2.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.064

2316
D. Dunn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2315–2317
O
S
b
a
S
OH
+
S
NH2
NH
X
H2N
NH2
I
6
7
I
I
X = OH
X = NH2
c
5
4
3
d
O
S
O
B(OH)2
(-) 2
e
O
O
S
f
NH2
+
NH2
I
Cl
(+) 2
Cl
2
8
9
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, room temp, 2 h, 90%; (e) tetrakis
(triphenylphosphine)Pd, 2 M Na2CO3, EtOH–toluene, 80 °C, 3 h, 80%; (f) HPLC-separation utilizing chiral AS column eluting with CH3CN.
Table 1
Transporter binding/uptake inhibition data for compounds 1, ( )-2, (ꢀ)-2 and (+) 2.
Assay
1
( )-2
(ꢀ)-2
0.4
0.6
16% at 10
11
(+)-2
DAT binding, (rat IC50
lM)
3.7a
0.6a
4.2
3.8
12% at 10
32
4% at 10
>300
DAT uptake inhibition (rat IC50
NET binding, (rat% inhibition)
NET uptake inhibition (rat IC50
SERT binding, (rat% inhibition)
l
M)
M)
M)
4.3a
0.83a
NAb
10a
NAb
l
M
lM
l
63.9a
NAb
NAb
>300a
3% at 10
>300
l
M
lM
SERT uptake inhibition (rat IC50
l
>300a
a
From Ref. 5.
Not available.
b
Table 2 displays activity of the enantiomers against various
CYP450 isoforms, indicating drug–drug interaction in a clinical set-
ting might not be a potential issue for the pair.
In the rat wake promotion assay (Table 3), both compounds dis-
played activity. Detailed mechanistic studies will be needed to an-
swer to the question of relative contributions of the transporters in
explaining their individual activity.8 Each enantiomer is currently
being evaluated in various behavioral assays.
In conclusion, in this Letter we disclosed various characteristics
of the enantiomers of racemate compound 2 from our ongoing
studies in order to identify a next generation molecule to the novel
wake promoting agent modafinil. Both compounds are currently
being evaluated in various behavioral assays, results of which will
be the subject of future publications.
Table 2
CYP450 Inhibition data (human microsome) for compounds 1, ( ) 2, (ꢀ) 2 and (+) 2.
Assay
1 (IC50
lM)
( )-2 (IC50
M)
(ꢀ)-2 (IC50
M)
(+)-2 (IC50
M)
l
l
l
2C19
3A4/5
11a
<10%
@10
19a
<10%
@10
174
139
112
159
l
Ma
l
Ma
2D6
<10%
<10%
177
151
@10
NAb
NAb
l
Ma
@10
NAb
NAb
l
Ma
2C9
1A1/2
233
14% at
129
20% at
100
lM
100 lM
a
From Ref. 5.
Not available.
b
Acknowledgments
Table 3
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. Authors sincerely
thank one of the reviewers for constructive criticism and sugges-
tions to improve the quality of the manuscript.
Wake promoting activity of compounds 1, ( )-2, (ꢀ)-2
and (+)-2.
Compound
Rat wake 4 h AUC Minutesa
1b
117 13⁄
176 4⁄
( )-2b
(ꢀ)-2
(+)-2
Vehiclec
238.5 0.8⁄
227.1 7.8⁄
79.2 7.2
References and notes
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
www.provigil.com (accessed on 22.12.11.).
2. Andersen, M. L.; Kessler, E.; Murnane, K. S.; McClung, J. C.; Tufik, S.; Howell, L. L.
Psychopharmacology 2010, 210, 439.
a
b
c
Mean SEM; ⁄P < 0.05 versus vehicle.
Data represents 3 h AUC (minutes).5
Average of vehicle group: N = 3–4 per group.

D. Dunn et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2315–2317
2317
3. Volkow, N. D.; Fowler, J. S.; Logan, J.; Alexoff, D.; Zhu, W.; Telang, F.; Wang, G. J.;
6. Physical properties: (ꢀ) 2: mp 175–176 °C; optical rotation: ½a D20
ꢁ
ꢀ69° (c = 0.3%
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.
MeOH). (+) 2: mp 175–176 °C; optical rotation: ½a D20
+69° (c = 0.3% MeOH).
ꢁ
7. A report of an asymmetric synthesis of individual enantiomer has recently been
disclosed in following granted patent: US 7,893,111, 2011.
8. In order to delineate the mechanism of action of modafinil, following
publication describing several of its analogs recently 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.
5. Dunn, D.; Hostetler, G.; Iqbal, M.; Messina-McLaughlin, P.; Reiboldt, A.; Lin, Y. G.;
Gruner, J.; Bacon, E. R.; Ator, M. A.; Chatterjee, S., Bioorg. Med. Chem. Lett. in
press, doi:10.1016/j.bmcl.2011.12.099.