Discovery of diphenyl lactam derivatives as N-type calcium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2011.12.100

A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration.

Full text of DOI:10.1016/j.bmcl.2011.12.100

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1716–1718
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Bioorganic & Medicinal Chemistry Letters
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Discovery of diphenyl lactam derivatives as N-type calcium channel blockers
⇑
George A. Doherty , Pramila Bhatia, Timothy A. Vortherms, Kennan C. Marsh, Jill M. Wetter,
Helmut Mack, Victoria E. Scott, Michael F. Jarvis, Andrew O. Stewart
Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, IL 60064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies
resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds
2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following
oral administration.
Received 5 November 2011
Revised 16 December 2011
Accepted 20 December 2011
Available online 8 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-type calcium channel blockers
Voltage-gated calcium channels
Voltage-gated calcium channels (VGCC) play an integral role in
the regulation of membrane ion conductance, neurotransmitter
release and cellular excitability in neurons. VGCC are classified into
low-voltage activated (T-Type) and high-voltage activated (L, N, P/
Q and R-Types) channels. Inhibition of T- or N-type calcium chan-
nels leads to analgesia through modulation of neuronal membrane
excitability and neurotransmitter release, respectively.1 Zicono-
tideÒ (Prialt™) is a peptide toxin that potently binds to the pore re-
gion of the N-type calcium channel irrespective of the channel’s
conformational state (open, closed, or inactivated). It is adminis-
tered to patients via intrathecal delivery and provides symptom-
atic relief of severe chronic pain in patients for which opioid
therapy is no longer effective.2–4 Unlike opioids, prolonged expo-
sure to ZiconotideÒ does not lead to the development of addiction
or analgesic tolerance. These positive clinical results have encour-
aged us and others to focus on developing orally bioavailable small
molecule N- and T-type calcium channel blockers for analgesia.
The diphenylmethylpiperazine scaffold has been established as
a key structural element which contributes to the calcium binding
affinity of a variety of identified calcium channel blockers.5 High
throughput screening of the Abbott compound collection led to
the discovery of compound 1. Due to the structural similarities of
this compound with the previously reported calcium channel
blockers NP078585 and NP18809,6,7 we hypothesized that the
diphenyl lactam of compound 1 was acting as a bioisosteric
replacement for the diphenylmethylpiperazine group (Fig. 1). Thus,
the diphenyl lactam group has the potential to be a novel and
general calcium channel binding scaffold.
The chemistry for the synthesis of the diphenyl lactams is
described below (Scheme 1). Both the five and six member lactams
were prepared from the corresponding diphenylacetic acid esters
F
OMe
OMe
O
N
N
N
N
OMe
F
NP078585
NP118809
OMe
OMe
O
N
N
1
N
OMe
Figure 1. Structures of compound 1, NP078585 and NP118809.
R
O
NH
R
R
CO2Me
R
O
R
NH
R
⇑
Corresponding author.
E-mail address: george.doherty@abbott.com (G.A. Doherty).
Scheme 1. Reagents and conditions: (a) LiHMDS, chloroacetonitrile, 90%; (b)
sodium methoxide, acrylonitrile, 70%; (c) Raney-Ni, MeOH/NH3, 93%.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.100

G. A. Doherty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1716–1718
1717
Table 2
R
R
R
Calcium channel activity of benzyl analogues
O
O
R
N
a,b
O
c
R1
OH
NH
N
R
N
R
R
O
O
N
R2
R
O
0,1
0,1
0,1
N
N
R1
O
Scheme 2. Reagents and conditions: (a) potassium tert-butoxide, ethyl bromoace-
tate, 93%; (b) LiOH, ethanol, water, 85%; (c) amine, EDC, DMAP.
n
Compounds
n
R1 R2
N-Type FLIPR pIC50 SEM (IC50, l
M)a
10
11
0
0
H
H
4-F-phenyl
5.65 0.01 (2.22)
5.99 0.01 (1.03)
3-CF3-
phenyl
2,4-Cl-
phenyl
2,6-Cl-
phenyl
3-CF3-
phenyl
3-Cl-phenyl
2,4-Cl-
phenyl
3-CF3-
phenyl
4-CF3-
phenyl
3-CF3-
phenyl
via alkylation of the enolate with either chloroacetonitrile for the
five membered lactam or acrylonitrile or the six membered lactam.
Reduction of the corresponding nitrile to the amine occurred with
Raney-Ni which underwent cyclization to the lactam upon further
heating. The 4-fluoro substituted diphenyl lactams (R = F) also effi-
ciently underwent this progress which gave access to the corre-
sponding difluorophenyl lactams.
With both of the lactams in hand, incorporation of acetic acid
ester followed by hydrolysis completed the synthesis of the key
carboxylic acid building blocks. The acid was coupling with a vari-
ety of amines to give the target compounds (Scheme 2).
We initially explored a variety of benzyhydril piperazine ana-
logues (Table 1). The commercially available benylhydril pipera-
zines underwent smooth coupling reaction with the carboxylic
acid in the presence of EDC and DMAP. Both the five and six mem-
bered lactam analogues demonstrated similar potencies against
the N-type calcium channel and substitution of the phenyl rings
with either fluorine or chlorine to reduce the oxidative potential
of the aromatic rings was well tolerated. All of the benzyhydril
analogues demonstrated higher than ideal ClogP values (>6) and
12
13
14
0
0
0
H
H
F
6.28 0.03 (0.52)
6.04 0.05 (0.90)
6.00 0.12 (1.01)
15
16
1
1
H
H
5.88 0.08 (1.32)
5.75 0.02 (1.80)
17
18
19
1
1
1
H
H
F
6.03 0.11 (0.93)
5.86 0.04 (1.38)
5.87 0.06 (1.36)
a
All values are means SEM of at least 2–4 experiments each with two
replicates.
azine with either a 4-substituted piperadine or an azetidine pro-
vided compounds with similar potencies, while the 3-substituted
piperadines, tetrahydroisoquine analogue and substituted pyrroli-
dine all tended to loose activity relative to the piperazine analogue.
Although the potency was maintained for some of the piperazine
replacements, these were de-emphasized to do a lack of improve-
ment in drug-like qualities compared with the corresponding
piperazine analogues.
low aqueous solubility (<25 lM) at neutral pH.
We next looked at substituted benzyl piperazines (Table 2) with
the goal of removing a phenyl ring to reduce the overall lipophilic-
ity and improve the overall physicochemical properties of the ser-
ies. The simple fluorophenyl analogue showed a slight loss of
potency when compared with its benzyhydril counterpart (com-
pound 10 vs compound 4) but reduced the ClogP by 1.3 and im-
The compounds were profiled against both rat and human
microsomes in addition to routinely obtaining aqueous solubility
proved the aqueous solubility (57 lM). The potency was
recovered with a more lipophilic substituent on the phenyl ring
such as chlorine or trifluoromethyl group but at the cost of a smal-
ler reduction in the ClogP and less significant solubility
improvements.
Table 3
N-Type calcium channel activity
Substitution of the piperazine with other cyclic amines was
next explored (Table 3). The bioisosteric replacement of the piper-
O
R
N
O
, l
M)a
Table 1
Compounds
R
N-Type FLIPR pIC50 SEM (IC50
5.76 0.07 (1.74)
N-type calcium channel activity of benzylhydril analogues
Ph
R1
N
N
OH
20
R2
R3
Ph
Ph
O
N
N
21
5.58 0.13 (2.61)
N
Ph
R1
O
n
Ph
Ph
22
23
6.09 0.14 (0.81)
6.18 0.02 (0.66)
N
N
NH
Compounds
n
R1 R2
R3
N-Type FLIPR pIC50 SEM
(IC50
M)a
,
l
Ph
Ph
2
3
0
0
H
H
Phenyl
Phenyl
Phenyl
4-Cl-
6.14 0.12 (0.72)
5.99 0.19 (1.01)
N
N
Phenyl
4-F-
Phenyl
4-F-
phenyl
Phenyl
Phenyl
4-F-
phenyl
Phenyl
24
25
6.09 0.05 (0.81)
5.61 0.05 (2.43)
Ph
Ph
4
5
0
0
H
H
Phenyl
6.35 0.05 (0.45)
6.37 0.09 (0.43)
4-F-
Ph
Ph
phenyl
Phenyl
Phenyl
4-F-
phenyl
Phenyl
6
7
8
0
1
1
F
H
H
6.08 0.01 (0.83)
5.86 0.06 (1.38)
5.63 0.06 (2.36)
26
27
5.35 0.02 (4.44)
5.51 0.02 (3.07)
N
N
CF3
CF3
9
1
F
5.34 0.02 (4.61)
a
a
All values are means SEM of 2–6 experiments each with two replicates.
All values are means SEM of 2–4 experiments each with two replicates.

1718
G. A. Doherty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1716–1718
Table 4
HT-ADME
Substitution of the phenyl rings with halogens did not significantly
improve the metabolic stability indicating other sites for metabo-
lism beyond the aromatic groups.
Compounds RLM %Rem @ 30 min HLM %Rem @ 30 min Solubility
CLND
A number of compounds were selected for pharmacokinetic
profiling as shown in Table 5. The compounds did show higher
clearance values as expected based on the in vitro data, but due
to their high volumes of distributions, showed reasonable half-
lives of between 2.7 and 6.7 h. The compounds could be dosed or-
ally using a lipid formulation with bioavailability ranging between
15% and 50%.
2
6
7
11
17
22
0.4
2.0
0.1
0.1
1.2
<0.1
—
<2
<2
<2
18.9
15.9
7.3
2.5
0.1
0.3
0.1
<0.1
Compounds 2, 6 and 7 showed good N-type FLIPR activity and
modest oral bioavailability and were therefore assessed for antino-
cicpetive activity in the capsaicin model of secondary hyperalge-
sia8 at 30 mg/kg orally ( Fig. 2). Each compound significantly
reversed tactile allodynia induced by prior intraplantar administra-
tion of capsaicin. Additional studies of compound 7 indicate that
this N-type calcium channel block is selective versus L-Type cal-
cium channels and does not alter hemodynamic function in
rats.9,10 Further biological characterization of compound 7 and re-
lated analogues are currently ongoing.
Table 5
Rat PK for selected calcium channel blockers
Compounds t1/2 (h) Vss (L/kg) CLp (L/h/kg) %F
OralAUC (ng h/mL)
2a
5.6
7.2
5.2
2.7
6.3
6.9
13.2
5.8
5.9
11.4
1.6
2.2
1.5
2.5
2.7
16.4
20.3
16.6
159
160
186
6a
7a
17b
23b
15.6 1004
50.0 2989
a
3
5
lmol/kg IV dose and oral dose.
b
l
mol/kg IV dose and 30
l
mol/kg oral dose.
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0
veh
Cpd 6
Cpd 2
Cpd 7 Gabapentin
30 mg/kg p.o.
Figure 2. Compounds 2, 6 and 7 attenauted nociception in the Capsaicin model of
secondary mechanical hyperalgesia. Gabapentin (positive control) also reversed
tactile allodynia in this assay at 150 mg/kg, po compounds 2, 6 and 7 were dosed in
prepared in 10% PEG400/10% cremophor EL/80% oleic acid in a volume of 2 ml/kg.
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(Table 4). As expected, reducing some of the aromatic nature of the
compounds and lowering the ClogP yielded improvements in the
aqueous solubility but the microsomal stability was not improved.