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2651
when compared to 1, compound 2 strongly inhibited the
activity of CYP2D6. Various polar substituents were
introduced at the 2-, 3-, and 4-position of the phenacetyl
group of 1 in an attempt to reduce the CYP2D6 inhibi-
tory activity while maintaining potent j agonist activity.
Introduction of an aminomethylene side chain at the 4-
position of the phenacetyl group of 1 (compound 5) re-
sulted in a sevenfold decrease in the CYP2D6 inhibitory
activity. However, this structural modification also re-
sulted in a 10-fold decrease in j binding. Comparison
of the in vitro profile of 3, 4, and 5 suggested that sub-
stitution at the 4-position of the phenacetyl group is pre-
ferred to lower the CYP2D6 inhibitory activity, whereas
substitution at the 2- or 3-position is required for good j
binding affinity. Conversion of the aminomethylene
group of 5 to an acetamidomethylene moiety (com-
pound 8) resulted in a further decrease in the CYP2D6
inhibitory activity, with no enhancement of the j affin-
ity. However, changing the acetamidomethylene moiety
by a methylureamethylene group (compound 9) resulted
in an increase in j binding affinity. Surprisingly, substi-
tution of the amine functionality of 5 with a meth-
an important factor to disrupt the key interaction with
the CYP2D6 isoenzyme.
In further studies, compound 13 showed very little
inhibitory activity toward other drug-metabolizing
CYP enzymes (CYP1A2: 0% inh. @ 10 lM; CYP2C19:
25% inh. @ 10 lM; CYP2C9: 20% inh. @ 10 lM;
CYP3A4: 15% inh. @ 10 lM). With regard to ancillary
activity, 13 did not inhibit (0% block @ 10 lM) hERG
channel currents in vitro (experiments performed in
voltage-clamped HEK293 cells that stably expressed
hERG potassium channels). The blocking of this cardiac
K+ channel (Ikr) has been linked to drug-induced long
QT syndrome (LQT), which can lead to torsades de
pointes, a life threatening form of arrhythmia, and sub-
sequent ventricular fibrillation.21 Based on its favorable
in vitro profile, 13 was evaluated in an in vivo model of
antinociception. Compound 13 displayed potent antino-
ciceptive activity in the mouse acetic acid-induced writh-
ing assay after subcutaneous or oral administration
(ED50 values of 0.87 and 8.3 mg/kg, respectively).22
ylsulfonyl group (compound 12) resulted in
a
In summary, the new series of sulfonamido arylacet-
significant increase in the affinity toward the j receptor
and a marked decrease in the CYP2D6 inhibitory acti-
vity. Comparison of the in vitro profile of 10, 11, and
12 further confirmed that substitution at the 4-position
of the phenacetyl group is optimal to decrease CYP2D6
binding. Analysis of the docking results generated for 1
confirmed that there is ample space in the CYP2D6 ac-
tive site for substituents at the 2- and 3-position of the
phenacetyl group. In contrast, the CYP2D6 active site
is more constrained near the 4-position, accommodating
preferably small hydrophobic substituents (see Fig. 1).
Introduction of a hydroxyl group at the 3-position of
the pyrrolidine ring of the arylacetamide class of j-ago-
nists is known to enhance receptor affinity.17 Similarly,
in this series, potency at the j receptor was further in-
creased, by substituting the pyrrolidine ring of 12 with
a hydroxyl group (compound 13, R2 = OH). This modi-
fication also resulted in a further decrease in the
CYP2D6 inhibitory activity (IC50 > 10 lM), presumably
due to a decreased lipophilicity. With the identification
of 13 as a novel potent j agonist with reduced CYP2D6
liability, we investigated further the SAR at the 4-posi-
tion of the phenylacetamide group, concentrating on
sulfonamide derivatives. Among the various sulfon-
amides prepared (Table 2), the aliphatic substituted deriva-
tives (compounds 14–16) had better CYP2D6 profiles
than the aryl/heteroaryl sulfonamides (18–22), and still
maintained potent agonist activity at the j receptor.
The comparison of the CYP2D6 inhibitory activity of
13 and 23 suggested that the spatial orientation of the
methylsulfonamido moiety influences the CYP2D6
inhibitory activity of the compounds. Comparison of
the CYP2D6 inhibitory activity of 13, 23, 24, and 25
showed that an optimal CYP2D6 profile was obtained
when the methylsulfonamido group was attached to
the core arylacetamide template with a methylene linker
(compound 13). Comparison of the CYP2D6 profile of
12 (IC50 > 10 lM) with its constrained analog 26
(CYP2D6 IC50 = 1037 nM) further demonstrated that
flexibility of the methylsulfonylaminomethyl moiety is
amide j agonists provided ligands with reduced
CYP2D6 liability (e.g., 13: IC50 > 10 lM) compared to
the reference compound, ICI 199441 (1: IC50 = 26 nM),
from which they evolved. Introduction of an alkylsulfon-
amidomethylene group at the 4-position of the phen-
acetyl moiety was critical to disrupt the interaction of
the compounds with CYP2D6 while maintaining potent
j agonist activity. The flexibility of the sulfonamide side
chain played an important role in reducing the inhibi-
tory activity of the compounds toward CYP2D6.
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