Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

Article abstract of DOI:10.1016/j.bmcl.2010.04.052

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) includin

Full text of DOI:10.1016/j.bmcl.2010.04.052

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3788–3792
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin
and noradrenaline reuptake inhibitors: Improving metabolic stability
and reducing ion channel activity
b
a
c
d
M. Jonathan Fray a, Paul V. Fish a, , Gillian A. Allan , Gerwyn Bish , Nick Clarke , Rachel Eccles ,
Anthony C. Harrison b, Jean-Loic Le Net c, Stephen C. Phillips d, Nicola Regan c, Cecile Sobry c,
Alan Stobie a, Florian Wakenhut a, Dominique Westbrook d, Simon L. Westbrook d, Gavin A. Whitlock a
*
a Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
b Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
c Drug Safety Research and Development, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
d Genitourinary Biology, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake
inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter,
we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, car-
diovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism
in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could
be achieved by appropriate substitution of the phenyl rings (6: R; R1) combined with a preferred stereo-
chemistry. From this set of compounds, piperazine (À)-6a was identified as a potent and selective dual
SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based
on this profile, (À)-6a was selected for further evaluation in a preclinical model of SUI.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 March 2010
Revised 13 April 2010
Accepted 13 April 2010
Available online 18 April 2010
Keywords:
Serotonin and noradrenaline reuptake
inhibitor (SNRI)
Stress urinary incontinence
4-Piperazines
Metabolic stability
Ion channel activity
CYP2D6 metabolism
Dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibi-
tors (SNRI) have proven to be an effective treatment for a number
of indications including depression, anxiety disorders, fibromyalgia,
painful peripheral neuropathy and stress urinary incontinence.1,2
Stress urinary incontinence (SUI) is the loss of urine coincident
with an increase in intra-abdominal pressure on the bladder that ex-
ceeds the urethral resistance. Examples of triggers of involuntary
leakage of urine are coughing, sneezing, laughing and physical exer-
cise. There are believed to be 13 million sufferers of SUI in the US and
very few seek treatment.3 Until recently, there were no pharmaco-
therapies licensed for SUI and treatment was limited to the off-label
In the context of treating SUI, SNRIs are believed to work by
blocking reuptake of 5-HT and NA in Onuf’s nucleus in the sacral
spinal cord.4 Pudendal motor neurons located in Onuf’s nucleus
regulate the urethral striated muscle sphincter and Onuf’s nucleus
has a high density of 5-HT and NA receptors.4 Furthermore, it has
been reported that the prevention of urine leakage could be med-
iated by stimulation of central 5-HT2 and a1 adrenergic receptors
resulting in more effective closure of the urethral sphincter.6
MeO
NHMe
S
use of non-selective a-adrenergics (urethral tone), tricyclic antide-
NMe2
OH
O
pressants (urethral tone), b-adrenergics (bladder relaxant) and
estrogens (reverses atrophy).4 In 2004, Eli Lilly introduced dual SNRI
duloxetine (1) as the first licensed drug therapy specifically for the
treatment of moderate to severe SUI. Dual SNRI venlafaxine (2) has
also shown potential utility as a treatment for SUI.5
1: duloxetine
2: venlafaxine
The search for potent and selective SNRIs has identified duloxe-
tine (1),7 venlafaxine (2),8 desvenlafaxine9 and milnacipran10
which are all marketed drugs. Furthermore, several small molecule
* Corresponding author. Tel.: +44 (0)1304 644589; fax: +44 (0)1304 651987.
E-mail address: paul.fish@pfizer.com (P.V. Fish).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.052

M. J. Fray et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3788–3792
3789
SNRIs have been reported to be in early clinical development or
NH
NH
undergoing preclinical optimisation and evaluation.2,11 Our own
efforts have identified PF-184298 (3)12 which demonstrated robust
efficacy in a preclinical canine model of SUI and was selected for
clinical development.13 Along with benzamide 3, we have dis-
closed additional SNRIs based upon alternative chemical tem-
plates14–19 including PF-526014 (4).20 Piperazine 4 is a potent
dual SNRI with excellent selectivity over inhibition of dopamine
(DA) reuptake (DRI), weak inhibition of CYP450 enzymes, good
central nervous system (CNS) permeability, and minimal binding
activity at the hERG channel. However, 4 has moderate metabolic
stability in vitro in human liver microsomes (HLM) and modest
ion channel activity as measured by binding to representative
Na+ and Ca2+ channels.
Major pathway
N
N
CYP2D6 (44 %)
CYP3A4 (29 %)
CYP2C19 (21 %)
EtO
HO
4
5
Figure 2. In vitro metabolism of 4 in HLM.
individual CYP450 recombinant enzymes which identified that
CYPs 2D6, 3A4 and 2C19 (T1/2 2, 20, 60 min, respectively) should
be the major CYP450 enzymes contributing to the CYP-mediated
clearance of 4. Phenol 5 was subsequently shown to be a potent
dual SNRI (Table 1) although single dose pharmacokinetics in dog
showed minimal systemic exposure compared to parent (4:5, ratio
of Cmax >100:1).
H
N
Me
Me
NH
S
N
N
R
We proposed that second generation 4-piperazines 6 would
benefit from the blocking of sites vulnerable to metabolism as this
would help to improve metabolic stability. Suitable modifications
of this template 6 would be to exchange the 2-OEt group of 4 for
groups less prone to oxidative O-dealkylation and to introduce F-
atoms to prevent aromatic hydroxylation. In addition, a decrease
in compound lipophilicity was also likely to improve metabolic
stability and decrease ion channel activity; this reduction in lipo-
philicity would need to be balanced with retaining good CNS per-
meability. Hence, a detailed investigation of the structure activity
relationships (SAR) of the 4-piperazines 6 was undertaken with
the primary objective of retaining dual SNRI activity whilst opti-
mising metabolic stability and reducing ion channel affinity.
4-Piperazines 6 (Table 1) were conveniently prepared in a
three-step sequence as described previously (Scheme 1).20 Con-
densation of benzaldehydes 7, 1-Boc-piperazine 8 and benzotria-
zole in refluxing PhMe with azeotropic removal of water gave
intermediate 9, which was not isolated, but added directly as a
solution to the relevant benzylic Grignard or zinc reagent to afford
10.24 Deprotection of the N-Boc amines 10 with TFA furnished the
target compounds 6. Aryl ethers 6e and 6j were prepared from the
corresponding aryl iodides 11 by copper-catalysed coupling with
the appropriate aliphatic alcohol to give 12.25 The four pairs of sin-
gle enantiomers (Table 1) were prepared by separation of the cor-
responding racemic piperazines 6a, 6g, 6r and 6t by chiral HPLC.
Phenol 5 was prepared from 4 by chemical O-deethylation with
BBr3.
Target compounds 4–6 (Table 1) were tested for their ability to
inhibit specific binding of selective radioligands at the human 5-
HT, NA, and DA transporters utilising scintillation proximity assay
(SPA) technology and cellular membrane preparations generated
from recombinant HEK293 cells expressing a single monoamine
transporter.16 Compound lipophilicity was assessed by calculation
of partition coefficients (c log P; BioByte software v4.3). Selected
compounds were then screened for metabolic stability in HLM,
for CYP2D6 inhibition, and binding to the potassium hERG and so-
dium TTX-S channels as a measure of ion channel activity.
The SARs were initially focused around replacing the 2-OEt of 4
with alternative 2-alkyloxy groups 6a–e. Only the 2-OMe ether 6a
retained good dual SNRI activity along with minimal ion channel
activity. Cyclising the ethoxy group into a ring as 2,3-dihydroben-
zofuran 6f also possessed minimal hERG activity but was accompa-
nied by an erosion in NRI activity; hence 6f was a potent SRI with
>40-fold selectivity over NRI. Further SAR was directed at exploring
the introduction of F-atoms both onto the group at the 2-position
6g–h, directly onto the ring as a second substituent 6i–j, and as a
combination of these two strategies 6k. Several groups were
accommodated with 2-OCHF2 6g being superior. Substitution on
O
Cl
EtO
Cl
3: PF-184298
4: PF-526014
In this Letter, we present previously undisclosed data for 4
including performance in a canine in vivo model of SUI, cardiovas-
cular (CV) assessment, pharmacokinetics in dog and determination
of the primary routes of metabolism in vitro. In addition, we dis-
close our efforts to identify second generation dual SNRIs from this
N-(1,2-diphenylethyl)piperazine template 6 which have improved
metabolic stability and reduced ion channel activity.
The evaluation of 4 in a preclinical in vivo canine model of SUI
showed a robust dose-dependant response in improving urethral
tone that was at least as equivalent to duloxetine (1)13 and PF-
184298 (3)12 at similar free plasma concentration of drug.21 Piper-
azine 4 increased peak urethral pressure (PUP) by 38 4% at a free
plasma concentration of 2.7 nM (Fig. 1). The haemodynamic and
electrophysiological effects of 4 were examined in the isoflurane
anaesthetised dog (n = 4) using a stepped intravenous infusion reg-
imen which achieved free plasma concentrations of 30, 150, 400
and 1710 nM. The observed effects were consistent with the pri-
mary mode of action of an SNRI in this model.22
The metabolic stability of 4 was determined in HLM where 4
has a half-life (T1/2) stability of 70 min. The major metabolite was
identified as O-deethylation of the 2-OEt group to give phenol 5
(Fig. 2).23 Several minor metabolites were due to mono-oxidation
of the piperazine ring. The metabolism of 4 was investigated in
Figure 1. The effect of 4 on peak urethral pressure (PUP) as percent change relative
to control in the female anaesthetised dog (n = 5; iv infusion to steady state plasma
concentration). Each bar represents the mean response SEM versus mean free
plasma concentration. Significance relative to control noted thus *P <0.05. Dog
functional potency for 4: dSRI IC50 = 13 nM (platelet, n = 13); dNRI IC50 = 27 nM
(carotid artery, n = 16).

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M. J. Fray et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3788–3792
Table 1
In vitro inhibition of monoamine reuptake,a,b human liver microsomal stability,c CYP2D6 inhibition, sodium (TTX-S) and potassium (hERG) binding activity for piperazines 4–6d
NH
R
N
R1
4-6
Compoundd
R
R1
c log P SRI Ki (nM) NRI Ki (nM) DRI Ki (nM) HLM T1/2 (min) CYP2D6i IC50 (nM) Na+, TTX-S IC50 (nM) K+, hERG IC50 (nM)
1e
—
—
H
H
—
—
2-OEt
2-OH
4.3
3.6
4.2
3.0
5
6
10
8
45
21
12
58
435
544
2650
2070
3e
>120
70
>30,000
30,000
8550
790
20,000
6950
(À)-(R)-4e
(À)-(R)-5
>30,000
11,500
>10,000
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
H
H
H
H
H
H
H
H
H
2-OMe
2-OnPr
2-OiPr
2-OcPr
2-OCH2cPr
2,3-OCH2CH2– 3.7
2-OCHF2
2-OCF3
2-OMe; 3-F
2-OMe; 6-F
3.7
4.7
4.5
4.3
4.6
4
18
31
22
22
25
340
28
77
84
27
58
>10,000
1950
>3160
1390
1400
>3160
6560
>10,000
6810
2370
8740
41,000
5840
6370
6400
2960
21,400
10,700
10,900
20,800
8550
18
18
19
19
8
8
25
2
46
46
84
4.1
4.8
3.75
3.95
>120
109
>120
93
30,000
3600
>30,000
4700
2100
3810
6j
6k
9
19
2-OCHF2; 6-F 4.4
>3160
1830
10,400
6l
2-F 2-OMe
3-F 2-OMe
4-F 2-OMe
2-F 2-OCHF2
3-F 2-OCHF2
4-F 2-OCHF2
2-F 2-OCF3
3-F 2-OCF3
4-F 2-OCF3
3.8
3.8
3.8
4.3
4.3
4.3
4.9
4.9
4.9
10
8
8
17
12
9
21
16
15
97
30
100
46
26
40
46
30
51
>10,000
4060
4870
>10,000
3460
1760
>10,000
4900
5090
>120
>120
>120
91
117
92
>120
>120
>120
17,700
12,100
3840
4540
4830
3370
15,200
3660
3270
3990
3140
40,100
>22,500
16,000
6500
8240
9120
7600
6110
8050
6m
6n
6o
6p
6q
6r
6s
6t
(+)-6a
(À)-6a
(+)-6g
(À)-6g
(+)-6r
(À)-6r
(+)-6t
(À)-6t
H
H
H
H
2-OMe
2-OMe
2-OCHF2
2-OCHF2
3.7
3.7
4.1
4.1
4.9
4.9
4.9
4.9
16
2
6
27
34
24
36
24
83
12
30
180
116
17
200
30
4950
2940
3290
3160
>3160
>3160
2490
2620
>120
>120
72
20,000
>30,000
3000
4900
3100
3500
1400
3600
4470
5400
2970
4890
1410
39,000
22,900
12,700
15,300
2050
760
9640
4950
44
2-F 2-OCF3
2-F 2-OCF3
4-F 2-OCF3
4-F 2-OCF3
109
>120
81
2960
1420
>120
a
b
c
See Ref. 16 for details of assay conditions.
Monoamine reuptake Ki values are geometric means of typically 2–8 experiments. Differences of <2-fold should not be considered significant.
Maximum measurable half-life was 120 min.
Compounds 6 are racemic unless defined otherwise. Single enantiomers are designated by the sign of optical rotation, [a]D.
d
e
Data is presented for comparison in a common assay format.
the aryl ring (R) was investigated by the introduction of a F-atom at
the 2-, 3- and 4-positions in combination with preferred 2-aryloxy
groups (R1 = OMe; OCHF2) to give 6l–q. However, these offered lit-
tle advantage compared to the parent structures (6a vs 6l–n and
6g vs 6o–q). Although the 2-OCF3 group had modest SNRI activity
as a single substituent 6h, this activity could be boosted by up to
2-fold when combined with a F-atom on the distal aryl ring (6h
vs 6r–t).
Analysis of the multiple SARs from this compound set high-
lighted some general trends: (1) All compounds had good SRI activ-
ity (6a–t: Ki 6 25 nM); (2) Good NRI activity could be obtained (6a,
c–e,: Ki 6 25 nM) but this activity was more sensitive to both the
nature and the position of the R1 groups (e.g., 6f, 6i), and other sub-
stituents on the molecule (R) (e.g., 6l, 6n); (3) No compound dem-
onstrated any significant DRI activity (6a–t: Ki >1000 nM); (4)
CYP2D6 inhibition and binding to the hERG channel was minimal
for the more polar examples and generally tracked with increasing
lipophilicity; (5) good HLM stability could be achieved through
either lowering lipophilicity (e.g., 6a, 6g, 6i, 6l–n)(6a vs 4 vs 6b)
or by blocking sites vulnerable to metabolism (e.g., 6r–t).
Compounds 6a, 6g, 6r and 6t were then evaluated as the two
single enantiomers (e.g., (+)-6a and (À)-6a) so as to determine
the influence of absolute stereochemistry on SRI, NRI and DRI
activity (Table 1). Screening of these separate enantiomers showed
one enantiomer possessed more SRI and NRI activity resulting in
potent dual SNRI and this trend was observed for all four pairs
[(À)-6a, (+)-6g, (À)-6r and (À)-6t]. These enantiomers with potent
SNRI activity tended to have improved HLM stability but slightly
greater affinity for binding to the hERG channel. The SARs for
DRI, CYP2D6-i and Na+ channel activity were not dependant on ste-
reochemistry for these compounds.
Pharmacokinetic data for (À)-6a, (+)-6g and (À)-6t was gener-
ated in vitro and in vivo in dog (Table 2). These compounds all
had some improvement of metabolic stability in vitro in DLM com-
pared to 4. Following single intravenous administration, plasma
clearance of (À)-6a and (À)-6t was moderate relative to liver blood
flow resulting in an elimination half-life of 7.1 and 6.0 h, respec-
tively. The high clearance for (+)-6g in excess of liver blood flow
was not predicted by DLM stability in vitro and can be attributed
to non-microsomal clearance mechanisms. Compounds (À)-6a

M. J. Fray et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3788–3792
3791
Table 3
Boc
N
Physicochemical properties, in vitro inhibition of monoamine reuptake, ADME
Boc
N
profiles and ion channel affinities of 4 and (À)-6aa
R
a
R
N
4
(À)-6a
+
N
H
CHO
Physicochemical properties
Mw
c log P
log D7.4
TPSA (Å2)
pKa
N
N
N
310
4.2
1.5
24
296
3.7
1.0
24
7
8
9
9.2 and 4.0
NDd
Monoaminine reuptake inhibitionb
SRI, Ki (nM)
b or c
10
2
NRI, Ki (nM)
12
12
DRI, Ki (nM)
2650
2940
Boc
ADME profile
HLM, T1/2 (min)
H.hepatocytes, T1/2 (min)
CYP2D6 inhibition, IC50 (nM)
CYP3A4 inhibition, IC50 (nM)
Caco-2, AB/BA Papp  10-6 cm sÀ1
N
NH
R
R
70
80
>120
127
d
N
N
30,000
30,000
33/36
>30,000
19,400
29/37
R1
R1
Ion channel affinities
K+ hERG, IC50 (nM)
Na+ TTX-S, IC50 (nM)
6950
790
450
730
5010
>10,000
22,900
5400
2200
ND
5900
>10,000
10
11: R1 = 2-I
6
Na+ site 2, IC50 (nM)
c
Ca2+ L-site (diltiazem), IC50 (nM)
c
e
Ca2+ L-site (verapamil), IC50 (nM)
c
12: R1 = 2-OR2
Ca2+ L-site (DHP), IC50 (nM)
c
Scheme 1. General synthesis of 4-piperazines 6. Reagents and conditions:
(a) benzotriazole, PhMe, Dean–Stark apparatus, reflux; (b) ArCH2MgX, THF,
À78 °C?0 °C, 30 min; (c) ArCH2ZnX, THF, 20 °C; (d) TFA, CH2Cl2, rt; (e) R2OH, CuI
(10 mol %), 1,10-phenanthroline (20 mol %), Cs2CO3, Reacti-Vial sealed vessel,
90–120 °C.
a
See Ref. 16 for definition of terms and details of assay conditions.
Monoamine reuptake inhibition Ki values are geometric means of at least four
b
experiments. Differences of <2-fold should not be considered significant.
c
Data from Cerep (Bioprint™).
ND, not determined.
d
and (+)-6g distribute extensively into tissues as shown by the high
volumes of distribution.
In conclusion, we have identified second generation dual SNRI
N-(1,2-diphenylethyl)piperazines 6 which have improved meta-
bolic stability and reduced ion channel activity. Of the strategies
explored, reducing overall lipophilicity of the target compounds
proved to be more successful in furnishing compounds with an im-
proved balance of in vitro and in vivo activities.
Compound (À)-6a was then evaluated in additional in vitro
pharmacology and pharmacokinetic screens; the results are pre-
sented along with the data for 4 (Table 3). Compound (À)-6a is a
potent dual SNRI with excellent selectivity over DRI (>245-fold).
Compound (À)-6a had improved metabolic stability in both HLM
and human hepatocytes consistent with low predicted clearance,
weak CYP450 enzyme inhibition and good membrane permeability
as measured by transit performance in Caco-2 cell-line. Compound
(À)-6a had reduced ion channel activity compared to 4 as mea-
sured by binding to representative potassium, sodium and calcium
channels. In addition, (À)-6a showed minimal off-target activity
against a panel of 110 receptors, enzymes and ion channels (Cerep,
Bioprint™) with >100-fold selectivity in binding assays for all tar-
gets evaluated except for the 5-HT7 (Ki 840 nM) and sigma
(Ki 290 nM) receptors. Furthermore, (À)-6a was one of the least
lipophilic structures of those presented in Table 1.26 Based on this
profile, (À)-6a was selected for further evaluation in a preclinical
in vivo canine model of SUI.27
Acknowledgements
We thank Edel Evrard, Arnaud Lemaitre, Debbie Lovering,
Bhairavi Patel, Ed Pegden, Melanie Skerten and Miles Tackett for
compound synthesis. We are grateful to Doreen Davey, Jonathan
Duckworth, Ian Gurrell, Mark Lewis, Nicola Lindsay, Caroline Tolley
and Christine Tyman for additional screening data. We acknowl-
edge the excellent support of the Analytical Sciences group. PVF
wishes to thank Mark Holbrook and Neil Brunton for helpful sug-
gestions in the preparation of this manuscript.
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D. Curr. Drug Ther. 2007, 2, 161; (e) Mariappan, P.; Alhasso, A.; Ballantyne, Z.;
Grant, A.; N’Dow, J. Eur. Urol. 2007, 51, 67.
Table 2
In vitro and in vivoa dog pharmacokinetic data for 4, (À)-6a, (+)-6g and (À)-6t
4
(À)-6a
(n = 2)
(+)-6g
(n = 1)
(À)-6t
(n = 2)
(n = 2)
2. For a recent review, see: Whitlock, G. A.; Andrews, M. D.; Brown, A. D.; Fish, P.
V.; Stobie, A.; Wakenhut, F. In Top. Med. Chem., Vol. 4: Transporters as Targets for
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b
DLM, T1/2 (min)
4
90
6
75
63
92.5
17
96.5
Dog plasma protein
binding (%)
4. Zinner, N. R. Expert Opin. Invest. Drugs 2003, 12, 1559.
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Intravenous dose (mg/kg)
Elimination half-life,
T1/2 (h)
Plasma clearance,
Cl (ml/min/kg)
0.025
5.1
0.025
7.1
0.025
1.8
0.0075
6.0
30
21
87
19
Volume of distribution,
Vd (l/kg)
13.5
13.2
13.6
7.0
11. For reviews of new SNRI chemical entities, see: (a) Walter, M. W. Drug Dev. Res.
2005, 65, 97; (b) Huang, Y.; Williams, W. A. Expert Opin. Ther. Pat. 2007, 17, 889;
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a
Single intravenous administration to male beagle dog.
Dog liver microsomes (DLM). Maximum measurable half-life was 120 min.
b

3792
M. J. Fray et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3788–3792
disclosures of dual SNRIs, see: (d) Vu, A. T.; Cohn, S. T.; Terefenko, E. A.; Moore,
W. J.; Zhang, P.; Mahaney, P. E.; Trybulski, E. J.; Goljer, I.; Dooley, R.; Bray, J. A.;
increase in PUP was used as a measure of efficacy of the drug in improving
urethral tone.
Johnston, G. H.; Leiter, J.; Deecher, D. C. Bioorg. Med. Chem. Lett. 2009, 19, 2464.
12. Wakenhut, F.; Allan, G. A.; Fish, P. V.; Fray, M. J.; Harrison, A. C.; McCoy, R.;
Phillips, S. C.; Ryckmans, T.; Stobie, A.; Westbrook, D.; Westbrook, S. L.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2009, 19, 5078.
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publishing, in press.
14. Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med.
Chem. Lett. 2007, 17, 2022.
15. Whitlock, G. A.; Blagg, J.; Fish, P. V. Bioorg. Med. Chem. Lett. 2008, 18, 596.
16. Fish, P. V.; Deur, C.; Gan, X.; Greene, K.; Hoople, D.; Mackenny, M.; Para, K. S.;
Reeves, K.; Ryckmans, T.; Stiff, C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2008, 18, 2562.
22. Both heart rate (HR) and cardiac contractility (LV+dP/dt) increased at the
lowest free plasma concentration (30 nM) by 23 beats/min and 815 mmHg/s,
respectively, compared with pre-dose. Thereafter the tachycardia decreased
towards pre-dose values and at the highest plasma concentration HR fell
rapidly to 27 beats/min below pre-dose values. Similarly, LV+dP/dt fell at free
plasma concentrations of 150 and 400 nM and by the highest concentration
1710 nM was 785 mmHg/s below pre-dose levels.
23. Phenol 5 was also the major metabolite in vitro when 4 was incubated with rat
and dog liver microsomes.
24. The benzylic halides 13 are commercially available except for 13f which was
prepared as shown.
Cl
CO2H
17. Whitlock, G. A.; Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F. Bioorg. Med.
Chem. Lett. 2008, 18, 2896.
18. Wakenhut, F.; Fish, P. V.; Fray, M. J.; Gurrell, I.; Mills, J. E. J.; Stobie, A.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2008, 18, 4308.
1. LiAlH4, THF
O
O
2. SOCl2, CH2Cl2
19. Fish, P. V.; Andrews, M. D.; Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2009, 19, 2829.
20. (a) Fray, M. J.; Bish, G.; Brown, A. D.; Fish, P. V.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2006, 16, 4345; (b) Fray, M. J.; Bish, G.;
Fish, P. V.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem. Lett.
2006, 16, 4349.
21. The evaluation of test compounds in a preclinical in vivo canine model of SUI
has been reported previously, see: Conlon, K.; Christy, C.; Westbrook, S.;
Whitlock, G.; Roberts, L.; Stobie, A.; McMurray, G., J. Pharm. Exp. Ther., 2009,
330, 892. In brief, test compounds were administered by iv infusion to
anaesthetized female dogs and a pressure transducer inserted into the urethra
as far as the bladder neck. The transducer would then be slowly withdrawn
whilst recording the pressure, and a measurement of peak urethral pressure
(PUP) would be taken: the percentage difference in PUP over vehicle was
plotted against steady state free plasma concentrations of drug. The percentage
13f
25. Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973.
26. For an analysis of the influence of drug lipophilicity on off-target pharmacology
and in vivo toxicological outcomes, see: (a) Leeson, P. D.; Springthorpe, B. Nat.
Rev. Drug Disc. 2007, 6, 881; (b) Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; De
Crescenzo, G. A.; Dalvie, D.; Devraj, R. V.; Doubovetzky, M.; Ellsworth, E.;
Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Grant, D.; Greene, N.; Huang, E.;
Kreiger-Burke, T.; Lee, L.; Loesel, J.; Nahas, K.; Wager, T.; Whiteley, L.; Zhang, Y.
Bioorg. Med. Chem. Lett. 2008, 18, 4872.
27. For detailed experimental procedures for the preparation and characterisation
of (À)-6a, see: Bish, G.; Brown, A. D.; Fish, P. V.; Fray, M. J.; Stobie, A.;
Wakenhut, F.; Whitlock, G. A. WO Patent Application 068447, 2005.