P. Louvet et al. / European Journal of Medicinal Chemistry 54 (2012) 949e951
951
Table 2
Transporter binding/uptake inhibition data for compounds 1, (L)-16 and (D)-16.
Table 4
Wake promoting activity of compounds 1, (L)-16 and (D)-16.
Assay
1
(L)-16
(D)-16
Compound
Rat wake 3 h AUC Minutesa
DAT binding, (rat IC50 mM)
DAT uptake inhibition (rat IC50 mM)
NET binding, (rat % inhibition @10 mM)
NET uptake inhibition (rat IC50 mM)
SERT binding, (rat % inhibition @10 mM)
SERT uptake inhibition (rat IC50
3.70a
4.30a
NAb
0.20
1.10
48
1.30
30
0.90
1.10
39
3.10
24
1
117 ꢁ 13*
168 ꢁ 7.8
167 ꢁ 0.9*
79.2 ꢁ 7.2
(L)-16
(D)-16
Vehicleb
63.90a
NAb
mM)
>300a
31
33
a
Mean ꢁ SEM; *P < 0.05, **P < 0.001 vs. vehicle, unpaired t-test.
Average of vehicle group: N ¼ 3e4 per group.
a
b
Ref. 1.
Not available.
b
assay (rat), in NET uptake inhibition assay, both displayed some
level of activity. However, both displayed low level of activity in
SERT binding as well as uptake inhibition assay (rat).
Table 3
CYP450 inhibition data (human microsome) for compounds 1, (L)-16 and (D)-16.
Table 3 indicates that both (L)-16 and (D)-16 exhibit better 2C19
profile than compound 1 as well as low levels of activity against
several other CYP450 isoforms, indicating drugedrug interactions in
a clinical setting might not be a potential issue for the pair.
In the rat wake promotion assay (Table 4), both (L)-16 and (D)-
16 displayed similar activity. Detailed mechanistic studies will be
needed to answer to the question of relative contributions of the
transporters in explaining their individual activity. Each enan-
tiomer is currently being evaluated in several behavioral assays.
Assay
1 IC50
11a
m
M
(L)-16 IC50 m
M
(D)-16 IC50 mM
2C19
3A4/5
2D6
2C9
1A1/2
30
40
106
216
20
32
89
2443
<10% @10
<10% @10
NAb
m
m
Ma
Ma
NAb
10% @100
m
M
18% @100 mM
a
Ref. 1.
Not available.
b
phenyl rings of the parent molecule maintaining the sufinylaceta-
mide moiety, thought to be unique for a CNS drug. In the current
series, they were attached by an ether linkage. A major effort was
expended in generating several ortho analogs (vide infra). As shown
in Table 1, compound 11 containing a 4-F substitution in ring B,
maintained the activity of reference compound 1. Replacement of
fluorine atom in compound 11 with chlorine atom produced
compound 12 that displayed superior activity compared to
compound 1. In a series of dichloro substituted ring B derivatives,
while 2,3- (compound 13), 2,4- (compound 14) and 3,5- (compound
15) substitution were not beneficial, 3,4- substitution (compound 16)
produced superior activity. Returning to the theme of 3,4-disubstition
in ring B, replacement of a chlorine atom with a fluorine atom
generated a pair of regioisomers, compounds 17 and 18 that main-
tained the superior activity. In a similar way, replacement of 3,4-
dichlorophenoxy moiety (ring B) with an isosteric 2-naphthyl group
generated compound 19 maintaining the superior activity compared
to compound 1. However, going from ortho-orientation to para-
orientation of two rings resulted in loss of activity (cf. compound 16
vs. compound 20). This observation prevented us to generate corre-
sponding meta-isomer.
4. Conclusion
In this Communication, we disclosed a series of diphenyl ether
derived wakefulness promoting agents (in rat). From this research,
racemic compound 16 emerged as a lead molecule and was sepa-
rated into enantiomers (L)-16 and (D)-16. Each enantiomer is
currently being evaluated in several behavioral assays.
Acknowledgment
Authors wish to acknowledge the scientific support and
encouragement of Drs. Donna Bozyczko-Coyne, John P. Mallamo
and Jeffry L. Vaught during the course of this research. Authors
sincerely thank all the reviewers for their constructive criticism and
valuable suggestions to improve the quality of the manuscript.
References
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