A novel series of pyrazolylpiperidine N-type calcium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2012.04.075

Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.

Full text of DOI:10.1016/j.bmcl.2012.04.075

CDCl3, 500 MHz, NOESY
d8 = 0.9 sec
ppm
NAME Compound 2
EXPNO
PROCNO
Date_
10
1
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
20120324
2.12
Time
INSTRUM
spect
PROBHD 5 mm PABBI 1H/
PULPROG
TD
noesyph
2048
CDCl3
SOLVENT
NS
56
4
DS
SWH
FIDRES
AQ
3004.808 Hz
1.467191 Hz
0.3410036 sec
128
RG
DW
166.400 usec
12.00 usec
298.2 K
DE
TE
d0
0.00015583 sec
2.00000000 sec
0.89999998 sec
0.00033280 sec
0
D1
D8
IN0
ST1CNT
======== CHANNEL f1 ========
NUC1
P1
1H
8.30 usec
6.00 dB
PL1
SFO1
ND0
TD
500.1323506 MHz
1
256
SFO1
FIDRES
SW
500.1324 MHz
11.737530 Hz
6.008 ppm
States−TPPI
1024
FnMODE
SI
SF
500.1300000 MHz
QSINE
WDW
SSB
LB
2
0.00 Hz
GB
0
PC
1.00
7.5
SI
512
MC2
SF
States−TPPI
500.1300000 MHz
QSINE
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
ppm
WDW
SSB
LB
2
0.00 Hz
GB
0

16
15
7
6
4
CDCl3, 500 MHz, NOESY
d8 = 0.9 sec
5
ppm
NAME Compound 2
EXPNO
PROCNO
Date_
10
1
20120324
2.12
6.3
6.4
6.5
6.6
6.7
6.8
6.9
7.0
7.1
7.2
7.3
7.4
7.5
7.6
Time
INSTRUM
spect
PROBHD 5 mm PABBI 1H/
PULPROG
TD
noesyph
2048
CDCl3
SOLVENT
NS
56
4
DS
SWH
FIDRES
AQ
3004.808 Hz
1.467191 Hz
0.3410036 sec
128
RG
DW
166.400 usec
12.00 usec
298.2 K
DE
TE
d0
0.00015583 sec
2.00000000 sec
0.89999998 sec
0.00033280 sec
0
D1
D8
IN0
ST1CNT
======== CHANNEL f1 ========
NUC1
P1
1H
8.30 usec
6.00 dB
PL1
SFO1
ND0
TD
500.1323506 MHz
1
256
SFO1
FIDRES
SW
500.1324 MHz
11.737530 Hz
6.008 ppm
States−TPPI
1024
H7 to H15
FnMODE
SI
SF
500.1300000 MHz
QSINE
WDW
SSB
LB
2
0.00 Hz
GB
0
PC
1.00
H7 to H15
SI
512
MC2
SF
States−TPPI
500.1300000 MHz
QSINE
7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3
ppm WDW
SSB
LB
2
0.00 Hz
GB
0