4286
C. Watson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4284–4287
Table 2
Table 4
Effect of C-2 substituent on hCB2 agonist activity
hERG activity in the optimisation of compound 23
O
O
Compound
hCB2 EC50 nM
hCB1 EC50 nM
hERG IC50 nM
c log P
S
N
N
R2
23
32
34
2.7
11
5.3
>10000
15000
ND
2600
63000
6200
3.5
2.7
3.4
Compound
R2
hCB2 EC50 nM
HLM Clint
RLM Clint
16
23
2.9
2.7
8.4
9
38
12
HLM Clint 12 µl/min/mg
RLM Clint 17 µl/min/mg
O
S
O
N
N
Rat PK (1mg/kg i.v):
Cl 27.1 ml/min/kg
Vd 1.0 L/kg
24
25
132
199
ND
43
ND
34
O
32
T
1/20.4h
425a
ND
ND
[brain]u:[plasma]u 1.0
26
Figure 4. PK properties of compound 32.
27
28
82
25
8.0
11
33
106
by weaker CB2 activity, resulting in a similar selectivity window for
both compounds. Pleasingly, compound 32 was a potent CB2 ago-
nist and selective with respect to CB1 with significantly reduced
hERG activity compared to 23. The in vivo clearance in rat was sim-
ilar to compound 23 and the oral bioavailability was once again
100% ( Fig. 4). Encouragingly, the [brain]u/[plasma]u in rat was
1:1, that is, 32 was fully CNS penetrant.
29
30
51
8.0
42
11
9.6
106
31
67b
ND
ND
In summary, the benzimidazole scaffold enabled identification
of novel, CNS penetrant CB2 agonists with excellent selectivity over
the CB1 receptor. We have identified compounds with similar
potency to lead compound 2 but with an improved PK profile.
Compound 23 is a useful tool compound to investigate the
pharmacology of brain penetrant selective CB2 agonists. Further
optimisation led to the discovery of compound 32, a CNS penetrant
selective CB2 agonist with reduced hERG activity. Further studies
are underway to assess the in vivo pharmacology of this compound
in pain models.
a
Emax 79%.
Emax 58%.
b
hCB2 EC50 2.7 nM
hCB1 Ki >20.0 µM
hCB1 EC50 >10.0 µM
Rat PK (1mg/kg i.v.):
Cl 20 mL/min/kg
Vd 3.2 L/kg
O
S
O
N
N
23
T
1/21.9h
Acknowledgments
Figure 3. Structure and properties of compound 23.
We would like to acknowledge the Pfizer Nagoya project team
for their discovery of the benzimidazole sulfone scaffold and their
work in this series.
Table 3
Effect of N substituent on hCB2 agonist activity
O
O
References and notes
S
N
N
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R3
3. Chaperon, F.; Thiebot, M.-H. Crit. Rev. Neurobiol. 1999, 13, 243.
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Compound
R3
hCB2 EC50 nM
HLM Clint
12
RLM Clint
17
O
32
33
11
106
8.0
8.5
34
35
5.3
39
7.0
8.0
19
OCF3
N
8.5
7. Kon-I, K.; Matsumizu, M.; Shima, A. U.S. 2006/0094750.
HLM and RLM. Their selectivity over CB1 and hERG is shown in
Table 4.
Compound 34 had similar a c log P to compound 23 and
although the hERG activity was slightly reduced, this was negated
8. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 19,
4406.
9. Kalvass, J. C.; Maurer, T. S.; Pollack, G. M. Drug Metab. Distrib. 2007, 35, 660.