Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine as selective noradrenaline reuptake inhibitors: Reducing P-gp mediated efflux by modulation of H-bond acceptor capacity

Article abstract of DOI:10.1016/j.bmcl.2008.06.071

Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.

Full text of DOI:10.1016/j.bmcl.2008.06.071

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4355–4359
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine as selective
noradrenaline reuptake inhibitors: Reducing P-gp mediated efflux by
modulation of H-bond acceptor capacity
b
b
a
a
a
Paul V. Fish a, , Nancy S. Barta , David L. F. Gray , Thomas Ryckmans , Alan Stobie , Florian Wakenhut ,
*
Gavin A. Whitlock a
a Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
b Discovery Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of nor-
adrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identi-
fied as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak
CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with
minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in
vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming
good CNS penetration.
Received 13 June 2008
Accepted 23 June 2008
Available online 25 June 2008
Keywords:
Noradrenaline reuptake inhibitor
NRI
Ó 2008 Elsevier Ltd. All rights reserved.
Carbamate
H-bond acceptor capacity
CNS penetration
Selective inhibition of noradrenaline reuptake (NRI) has been
shown to be an attractive approach for the treatment of a number
of diseases.1,2 For example, atomoxetine (1) is a new therapy for
the treatment of attention deficit hyperactivity disorder (ADHD)3
and reboxetine (2) is used clinically for the treatment of
depression.4
of exploring multiple chemical templates in order to increase our
chances of having compounds survive to become advanced clinical
candidates.
Cl
O
R2
O
2
Cl
Me
2
R3
N
S
3
N
3
Me
S
O
NHMe
NH
N
H
N
H
O
O
3
4
3a: R2 = R3 = Cl
3b: R2 = Ph; R3 = H
Me
EtO
1: atomoxetine
2: ( )-reboxetine
In this Letter, we disclose derivatives of (3S)-N-(biphenyl-2-
ylmethyl)pyrrolidin-3-amine as potent NRIs with good selectivity
over serotonin (5-HT) and dopamine (DA) reuptake inhibition
(SRI and DRI, respectively). Furthermore, factors that influence
P-glycoprotein (P-gp) transporter mediated recognition and efflux
are discussed.
We have reported several new templates that inhibit mono-
amine reuptake,5–11 and some of these compounds have now pro-
gressed to clinical trials.12,13 As part of our research efforts to
identify potential new NRI drug candidates, we adopted a strategy
N-(Benzyl)pyrrolidin-3-amines 3 were first disclosed as selec-
tive dual serotonin/noradrenaline reuptake inhibitors (SNRI) (e.g.,
3a).7 As part of this study, during the exploration of the SAR of
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.071

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P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4355–4359
Table 1
contrast to 3a, biphenyl 3b also possessed an unacceptable level of
CYP2D6 inhibition and so could potentially inhibit the metabolism
of CYP2D6 substrates.
In vitro inhibition of monoamine reuptake,a,b human liver microsomal stability and
CYP2D6 inhibition for compounds 3a, 3b and 4c
3a
3b
4
Further modification of this 3-aminopyrrolidine template by
acylation of the (3S)-amino group gave amides, for example,
4, with dual SNRI activity and modest inhibition of CYP en-
zymes (For 4: CYP1A2/2C9/2D6/3A4, <40% inhibition at
NRI, IC50 (nM)
SRI, IC50 (nM)
5
12
23
10
400
12
DRI, IC50 (nM)
89
100
4800
>4000
>120
100
1250
>120
>3000e
HLM, t1/2 (min)d
CYP2D6 inhib., IC50 (nM)
3 l
M).14 Hence, we elected to investigate replacing the 4-THP
group of 3b by amides and other amino derivatives with the
aim of retaining NRI activity whilst reducing the activity for
CYP2D6 inhibition.
Target compounds 8, 9, and 11–16 (Table 2) were prepared
using a short synthesis employing N-(benzyl)pyrrolidin-3-amines
7 as advanced intermediates (Scheme 1). This route allowed for
the selective functionalisation of the exocyclic sec-amine group
to afford a number of different amino derivatives viz. carboxam-
ides 9, carbamates 11, ureas 12, sulfonamides 13 and sulfonyl ur-
eas 14.
a
See Ref. 7 for complete details of assay conditions.
Monoamine reuptake IC50 values are geometric means of at least three exper-
b
iments. Differences of <2-fold should not be considered significant.
c
See Ref. 15 for definitions of terms and assays.
Maximum measured half-life was 120 min.
<10% inhibition at 3 lM.
d
e
the aryl ring, biphenyl compound 3b was identified as a potent NRI
with selectivity over SRI and DRI (>30-fold) (Table 1). However, in
Table 2
In vitro inhibition of monoamine reuptake,a,b human liver microsomal stability and CYP2D6 inhibition for compounds 8, 9, 11–16c,d
R2
R2
R2
X
X
X
N
N
N
R
N
N
N
H
H
Me
8, 9, 11-14
15
16
Compound
X
R2
NA Ki (nM)
5-HT Ki (nM)
DA Ki (nM)
HLM Cli (
l
L/min/mg)
CYP2D6-i IC50 (nM)
clogP
8
H
Ph
271
1070
2470
3.0
9a
9b
9c
9d
9e
9f
9g
9h
9i
–COH
–COMe
–COEt
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
c-Pr
CF3
SMe
OPh
118
124
30
25
6
30
70
74
63
65
34
869
5810
2680
730
960
415
544
124
133
50
2130
NT
NT
2610
3740
NT
3410
2920
NT
2.5
2.7
3.2
3.8
3.5
4.2
3.3
2.9
2.8
2.5
4.1
<7
<7
<7
<7
9
–COn-Pr
–COi-Pr
–COi-Bu
–COi-Pr
–COi-Pr
–COi-Pr
–COi-Pr
–COi-Pr
1860
<7
<7
10
9j
9k
1380
3500
229
11a
11b
11c
11d
11e
11f
–COOMe
–COOEt
–COOi-Pr
–COOEt
–COOEt
–COOEt
–COOEt
Ph
Ph
Ph
i-Pr
CF3
SMe
OPh
18
8
4440
1110
787
764
427
353
444
3190
3030
2010
3340
3210
NT
<7
<7
10,600
1210
3.7
4.2
4.5
4.0
3.5
14
49
46
89
23
11g
1900
21
420
4.7
12a
12b
–CONMe2
–CON(CH2)4
Ph
Ph
53
27
5010
NT
2970
4190
3.3
4.1
13a
13b
13c
13d
13e
13f
–SO2Me
–SO2Et
Ph
Ph
Ph
Ph
5
5
7
10
30
86
86
96
4120
5620
5680
4690
5280
2890
1250
2700
2670
2760
2070
2700
2080
2890
2950
2550
7
3100
1890
185
2.6
3.2
3.7
3.5
3.7
1.9
1.6
3.1
<7
12
20
–SO2n-Pr
–SO2i-Pr
–SO2CF3
–SO2Me
–SO2Me
–SO2Me
350
Ph
CF3
SMe
OPh
13g
13h
<7
16
14
–SO2NMe2
Ph
8
3330
2690
840
2.8
15a
15b
–SO2Me
–SO2Et
Ph
Ph
748
466
>10,000
>10,000
NT
NT
3.2
3.6
16a
16b
–COOEt
–SO2Me
Ph
Ph
16
29
410
5350
2910
2390
<7
<7
350
5360
4.2
2.6
a
See Ref. 9 for complete details of assay conditions.
Monoamine reuptake Ki values are geometric means of at least three experiments. Differences of <2-fold should not be considered significant.
NT denotes not tested.
See Ref. 15 for definitions of terms and assays.
b
c
d

P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4355–4359
4357
R2
O
R2
R2
R2
R2
O
NH
OR
N
N
R
N
H
N
N
H
H
8
9
11
b
d, b
c, b
f, b
R2
R2
O
CHO
NH2
N
Cl
a
e
N
NH
N
S
+
N
boc
boc
boc
5
6
7
10
h, i, b
j, k, b
h, b
g, b
R2
O
S
O
R2
O
S
N
NRR'
N
NRR'
N
R
O
O
N
N
N
H
H
H
14
13
15
12
l
Scheme 1. Synthesis of target compounds: amine 8, amides 9, carbamates 11, ureas 12, sulfonamides 13, sulfonyl urea 14, and N-methyl pyrrolidine derivatives 15. Reagents
and conditions: (a) MeOH, RT, then NaBH4, or NaBH(OAc)3, THF, RT; (b) TFA, CH2Cl2, RT; (c) RCOCl, NEt3, dioxane, RT; (d) ROCOCl, NEt3, dioxane, RT ? 70 °C; (e) triphosgene,
DMAP, NEt3, PhMe, RT; (f) ROH, NEt3, PhMe, RT ? 60 °C; (g) RR0NH, NEt3, PhMe, RT ? 60 °C; (h) RSO2Cl, NEt3, CH2Cl2, RT; (i) ArCH2Cl, NaOH, nBu4NHSO4, CH2Cl2–H2O, RT; (j)
R0RNSO2Cl, NEt3, CH2Cl2, RT; (k) ArCH2Br, NaOH, K2CO3, MeCN, reflux; (l) 37% aq HCHO, NaBH(OAc)3, CH2Cl2, RT.
Reductive amination of N-BOC-(3S)-aminopyrrolidine (6) with
benzaldehydes 5 under standard conditions gave benzylamines 7
and deprotection of the pyrrolidine N-BOC group afforded sec-
amines 8. Acylation of 7 with acyl chlorides and deprotection gave
amides 9. Carbamates 11 were prepared either by reaction of 7
with the alkyl chloroformate or by conversion of 7 to the carbam-
oyl chloride 10 with triphosgene and then reaction with the alco-
hol. Treatment of 10 with amines gave ureas 12. Methyl
sulfonamides 13 (R = Me) were prepared by reaction of 7 with Me-
SO2Cl, whereas all other sulfonamides 13 (R ¼ Me) were prepared
by conversion of 6 to the sec-sulfonamide followed by N-benzyla-
tion under standard conditions. Sulfonyl ureas 14 were prepared
from 6 by a similar two-step sequence of sulfonylation and then
benzylation. A few preferred sec-amines (13a, 13b) were converted
by N-methylation of the pyrrolidine ring to the corresponding tert-
amines (15a, 15b) by reductive amination employing standard
conditions. The (R)-enantiomers 16 were prepared by an identical
sequence but starting with N-BOC-(3R)-aminopyrrolidine.
technology and cellular membrane preparations generated from
recombinant HEK293 cells expressing a single monoamine trans-
porter.9 Selected compounds were then screened for metabolic sta-
bility in human liver microsomes (HLM) and for CYP2D6
inhibition.15
The sec-amine 8 had weak NRI activity showing that a second
N-substituent was required for activity. A series of carboxamides
9a–9f with alkyl groups of increasing size identified 9e with the
isopropyl group as the optimum N-substituent for NRI activity (Ki
6 nM). In addition, 9e had excellent selectivity over SRI and DRI,
good in vitro metabolic stability and weak CYP inhibition. Further
SAR was directed at improving NRI activity by exploring a broader
set of 2-substituents on the aryl ring 9g–9k. However, when com-
pared to 9e (i.e., R2 ¼ Ph), there was an erosion of NRI activity and
introduction of SRI activity leading to compounds with modest
dual SNRI activity (e.g., 9j). No compound demonstrated any signif-
icant DRI activity. The carboxamide group was successfully
exchanged for a carbamate 11a–11g with the Et group giving a
slight advantage in NRI activity and the preferred aryl substituent
was again the 2-Ph (11b). In contrast to the carbamates, the ureas
12a,b failed to yield a compound with potent NRI activity and were
Target compounds (Table 2) were tested for their ability to inhi-
bit specific binding of selective radioligands at the human 5-HT, NA
and DA transporters utilising scintillation proximity assay (SPA)

4358
P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4355–4359
not pursued. The sulfonamide derivatives 13a–13e showed good
NRI activity, and this SAR was more tolerant of different alkyl
groups. However, as the alkyl group increased in size and lipophil-
icity, there was a decrease in metabolic stability and the introduc-
tion of potent CYP2D6 inhibition (13a,b vs 13c,d). Sulfonyl urea 14
was a potent NRI but exhibited CYP2D6 inhibition and was not
pursued. Additional noteworthy NRI SARs was that N-methylation
on the pyrrolidine ring significantly reduced NRI activity (13a,b vs
15a,b) and the (R)-stereochemistry was slightly inferior to the (S)
(16a vs 11b, 16b vs 13a). A plot of NRI activity versus clogP
showed that excellent NRI activity could be achieved over a range
of lipophilicity (Fig. 1) as reduction of compound lipophilicity was
an important selection criteria.16 In conclusion, the (3S)-amino
group of 8 proved to be a versatile site to prepare amino deriva-
tives with potent NRI activity, excellent selectivity over SRI and
DRI, good in vitro metabolic stability and weak CYP inhibition.
From these experiments, carboxamide 9e, carbamate 11b and
sulfonamide 13a emerged as having a superior combination of
NRI activity (Ki < 10 nM) combined with selectivity over SRI and
DRI (>100-fold).
Additional screening of 9e, 11b and 13a in high throughput in
vitro ADME and safety screens showed all three compounds to
have excellent metabolic stability in HLM and human hepatocytes
consistent with low predicted clearance, weak CYP450 enzyme
inhibition and modest ion channel activity as measured by binding
to representative potassium, sodium and calcium channels (Table
3).15 An in vitro screen that clearly differentiated 9e, 11b and
13a was transit performance in the MDCK-mdr1 cell line which
is commonly used as a model to estimate CNS penetration.17 All
three compounds have good passive permeability but amide 9e
and sulfonamide 13a demonstrate efflux ratios (ER > 5) which
were consistent with recognition and efflux by the P-glycoprotein
(P-gp) transporter. Compounds with significant efflux by P-gp tend
to have poorer CNS penetration than compounds that are not.17
Performance in this assay proved to be decisive in selecting carba-
mate 11b for in vivo assessments of CNS penetration.
Compounds 9e, 11b and 13a had drug-like physicochemical
properties consistent with CNS target space (Table 3).17,18 Further-
more, many of these properties are quite similar and so the supe-
rior performance of 11b in the MDCK-mdr1 screen was not easy to
rationalise.19 We concluded that carbamate 11b offered the advan-
tage of slightly increased lipophilicity and lower H-bond acceptor
strength resulting in minimal recognition and efflux by the P-gp
transporter.20
1000
750
500
H-bond donor and acceptor profiles are key properties when
designing potential CNS drug candidates. However, HBD and HBA
counts may be too simplistic to distinguish between close struc-
tural analogues as HBD and HBA strengths of different functional
groups are not equivalent. We found that H-bond strengths, as
measured by Abraham et al.21 and Laurence,22 proved to be a valu-
able guide in ranking the HBA capacity of functional groups and
target compounds (Table 4).
Compound 11b was screened for off-target pharmacology
against a panel of 110 receptors, enzymes and ion channels (CEREP,
Bioprint) and was found to have binding affinity for the muscarinic
(M3) and 5-HT2A/2B/2C receptors (>80% inhibition at 10 lM). Further
evaluation showed 11b to be 80-fold selective over M3 (Ki 635 nM)
250
100
75
50
25
10
5
2
2.5
3
3.5
4
4.5
CLogP
and to have no confirmed functional activity at 5-HT2A/2B/2C
Figure 1. Plot of NRI activity versus clogP for all 34 compounds in Table 2.
(EC50 > 10 lM).
Pharmacological evaluation in vivo, in microdialysis experi-
ments,23 showed 11b increased NA levels in interstitial fluid of
the prefrontal cortex of conscious rats by 400% above pre-drug
baseline levels confirming good CNS penetration (Fig. 2).24
Table 3
Physicochemical properties, ADME profiles and ion channel affinities of 9e, 11b and
13aa,b
9e
11b
13a
Physicochemical properties
mw
clogP
322
3.5
1/3
0.8
NTc
32
324
4.2
1/4
1.1
9.6
42
330
2.6
1/4
0.6
8.9
58
Table 4
HBD/HBA count
logD7.4
pKa
Correlation of MDCK-mdr1 transit properties with HBA strength of the N-substituent
(X) (pKHB) for 9e, 11b, 12b, 13a and 14a,b
Ph
TPSA (Å2)
X
N
ADME profiles
HLM, Cli (
l
L/min/mg)
L/min/mg)
<7
NT
<7
<5
7
<5
h.heps, Cli (
l
CYP1A2 inhib., IC50 (nM)
CYP2C9 inhib., IC50 (nM)
CYP2D6 inhib., IC50 (nM)
CYP3A4 inhib., IC50 (nM)
CaCO-2, AB/BA
>3000
>3000
1860
>3000
NT
>3000
>3000
1210
>3000
27/28
22/44
2.0
>3000
>3000
3100
>3000
NT
N
H
c
Compound
X
logD7.4
MDCK-mdr1
AB/BA ER
6.1
2.0
26
pKHB
MDCK-mdr1, AB/BA
MDCK-mdr1, ER
11/68
6.1
10/51
5.1
9e
–COi-Pr
–COOEt
–CON(CH2)4
–SO2Me
–SO2NMe2
0.8
1.1
0.7
0.6
1.0
11/68
22/44
2/53
2.26
1.83
2.44
1.30
1.47
11b
12b
13a
14
Ion channel affinities
K+, hERG, Ki (nM)
2840
>10,000
1200
2830
1500
1100
>2700
1900
1900
10/51
17/68
5.1
4.0
Ca2+, L-type, Ki (nM)
Na+, site 2, Ki (nM)
a
See Ref. 15 for definitions of terms and assays.
Compounds 12b and 14 have been included in this analysis to expand the
a
b
See Ref. 15 for definitions of terms and assays.
NT denotes not tested.
pKa ꢀ 9.4 by analogy with the measured value for 4.
b
c
structural diversity of this data set.
c
See Ref. 22 for the origin of the pKHB values.

P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4355–4359
4359
6. (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.
7. Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med.
Chem. Lett. 2007, 17, 2022.
8. Whitlock, G. A.; Blagg, J.; Fish, P. V. Bioorg. Med. Chem. Lett. 2008, 18, 596.
9. 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.
10. Whitlock, G. A.; Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F. Bioorg. Med.
Chem. Lett. 2008, 18, 2896.
11. Fish, P. V.; Ryckmans, T.; Stobie, A.; Wakenhut, F. Bioorg. Med. Chem. Lett. 2008,
18, 1795.
12. Middleton, D. S. Abstracts of Papers, 230th ACS National Meeting, Washington,
DC, United States, Aug 28–Sep 1, 2005, MEDI-288.
13. Whitlock, G. A.; Wakenhut, F.; Stobie, A.; Fish, P. V.; Fray, M. J. Abstracts of
Papers, 233rd ACS National Meeting, Chicago, IL, United States, March 25–29,
2007, MEDI-019.
14. (a) Andrews, M. A; Brown, A. B.; Fish, P. V.; Fray, M. J.; Lansdell, M.; Ryckmans,
T.; Stobie, A.; Wakenhut, F.; Whitlock, G. A.; Gray D. L. WO Patent 064351,
2006.; (b) Wakenhut, F.; Fish, P. V.; Fray, M. J.; Stobie, A.; Whitlock, G. A. Bioorg.
Med. Chem. Lett. 2008, 18, 4308.
15. Definitions of terms and assays. clogP: calculated partition coefficient (BioByte
software). HBD: H-bond donor count (NH + OH); HBA: H-bond acceptor count
(N + O). logD7.4
: measured octanol-buffer distribution coefficients. TPSA:
Figure 2. Dose-dependent effects of 11b on NA levels in microdialysate from the
prefrontal cortex of conscious rats. Test compounds were administered sc at
time = 0 (n = 5–6). Atomoxetine (ATX, 1) was used as a positive control.
topological polar surface area. The minimum measurable intrinsic clearance
(Cli) in human liver microsomes (HLM) and human hepatocytes (h.heps) was 7
and 5 lL/min/mg protein, respectively. CYP: cytochrome P450 enzyme family
with isoenzymes 1A2, 2C9, 2D6, 3A4. CaCO-2: human colon adenocarcinoma
cell line. MDCK-mdr1: Madin-Darby canine kidney cell line expressing the P-
glycoprotein transporter (P-gp). Flux across cells was measured at 10 lM
In summary, derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrr-
olidin-3-amine are potent NRIs with good selectivity over SRI
and DRI. Carboxamide 9e, carbamate 11b and sulfonamide 13a
were identified as potent NRIs with excellent selectivity over SRI
and DRI, good in vitro metabolic stability and weak CYP inhibition.
Carbamate 11b demonstrated superior transit performance in
MDCK-mdr1 cell lines with minimal P-gp efflux which was attrib-
uted to reduced HBA capacity of the carbamate group. Evaluation
in vivo, in rat microdialysis experiments, showed 11b significantly
increased NA levels confirming good CNS penetration. Based on
this profile, 11b (PF-3609113)25 was selected as a candidate for
further evaluation in pre-clinical disease models.
substrate concentrations. Figures quoted correspond to the flux rates
(Papp ꢁ 10ꢂ6 cm sꢂ1) for apical to basolateral (AB) and basolateral to apical
(BA) directions. Efflux ratio (ER) is the BA/AB value. Ion channel screening:
potassium (K+), hERG ([3H]-dofetilide); sodium (Na+), (site 2); calcium (Ca2+
(L-type diltiazem site).
)
16. Preferred examples in Table 2 had calculated properties for ligand efficiency
(LE P 0.45) and ligand-lipophilic efficiency (LLE P 5.0) consistent with drug-
like chemical space. For an analysis of drug-like concepts, especially
lipophilicity, see: Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Dis. 2007, 6, 881.
17. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampine, L.
J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. J. Pharmacol. Exp. Ther. 2002,
303, 1029.
18. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 1.
19. The CNS analysis was limited by an incomplete set of in vivo data and so the
correlation was performed against performance in the in vitro MDCK-mdr1 cell
line.
20. For a substrate model of the P-gp transporter, see: Seelig, A. Eur. J. Biochem.
1998, 251, 252.
Acknowledgments
21. (a) Abraham, M. H.; Duce, P. P.; Prior, D. V.; Barratt, D. G.; Morris, J. J.; Taylor, P.
J. J. Chem. Soc., Perkin Trans. 1989, 2, 1355; (b) Abraham, M. H.; Grellier, P. L.;
Prior, D. V.; Morris, J. J.; Taylor, P. J. J. Chem. Soc., Perkin Trans. 1990, 2, 521.
22. The relative H-bond acceptor strengths of the N-substituents (X) were taken by
analogy with published values of related compounds (pKHB): Me2NCOi-Pr
(2.26); Me2NCOOEt (1.83); Me2NCONMe2 (2.44); Me2NSO2Me (1.30);
Et2NSO2NEt2 (1.47). See: (a) Laurence, C.; Berthelot, M. Persp. Drug Disc. Des.
2000, 18, 39 and references therein; (b) Graton, J.; Berthelot, M.; Laurence, C. J.
Chem. Soc., Perkin Trans. 2001, 2, 2130.
We thank Paul Blackwell, Tim Buxton, Bradley Caprathe, Russell
Cave, Soochal Kim and Yann Lecouturier for compound synthesis.
We are grateful to Stephen Phillips (Discovery Biology), Fidelma
Atkinson (PDM) and Robert Webster (PDM) for screening data.
References and notes
23. Deecher, D. C.; Beyer, C. E.; Johnston, G.; Bray, J.; Shah, S.; Abou-Gharbia, M.;
Andree, T. H. J. Pharmacol. Exp. Ther. 2006, 318, 657.
24. Rat NA functional transporter activity was measured in HEK293 cells
expressing the rat NA transporter with [3H]-NA as substrate. For 11b, rNRI,
Ki = 2.5 nM (n = 2).
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25. Data for 11b: [a]D = ꢂ4.9° (MeOH; c 0.19); >99% pure by HPLC; 100% ee by
chiral HPLC. For 11b HCl salt: 1H NMR (CD3OD, 400 MHz) d 1.20 (3H, t), 2.10–
1.98 (2H, br m), 3.10 (1H, m), 3.25 (1H, m), 3.34 (1H, m), 3.52 (1H, m), 4.06 (2H,
d), 4.14–3.92 (1H, br), 4.55 (2H, q), 7.28–7.10 (9H, m); LRMS APCI m/z 325
(MH+). For 11b D-tartrate salt: mp 117 °C.