Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.07.020

A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.

Full text of DOI:10.1016/j.bmcl.2011.07.020

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5310–5314
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Strategies to lower the Pgp efflux liability in a series of potent indole azetidine
MCHR1 antagonists
Kai Lu a, Yu Jiang a, Bin Chen a, Eman M. Eldemenky a, Gil Ma a, Mathivanan Packiarajan a,
Gamini Chandrasena a, Andrew D. White a, Kenneth A. Jones b, Boshan Li b, Sang-Phyo Hong a,
⇑
a Department of Chemical and Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA
b Synaptic Transmission Disease Biology Unit, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to
Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational
flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while
maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify
1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 May 2011
Revised 6 July 2011
Accepted 6 July 2011
Available online 14 July 2011
Keywords:
MCH
Pgp
Indolyl azetidine
Dihydroindolyl azetidine
CNS penetration
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide
consisting of 19 amino acids originally isolated from the pituitary
gland of the salmon.1 MCH is produced predominantly by neurons
in the lateral hypothalamus and zona incerta which project broadly
throughout the brain of mammals.2 The biological function of MCH
is mediated by its interaction with two G protein-coupled recep-
tors known as MCHR1 and MCHR2.3 Over the last 20 years, studies
have suggested that MCH plays a key role in the regulation of food
intake and stress in rodents.4 For example, ICV injection of MCH
reportedly stimulates food intake5 and chronic administration re-
sults in an increase in body weight.6 The link between MCHR1
and the function of MCH on feeding is illustrated with several stud-
ies on MCHR1 KO mice. These mice lacking the gene encoding MCH
are lean, hypophagic and maintain an elevated metabolic rate.7
Conversely, mice over-expressing the MCH gene are susceptible
to obesity and insulin resistance. In addition, MCH seems to play
a role in the regulation of mood and stress. A number of groups
have disclosed high affinity MCHR1 antagonists with efficacy in
behavioral models of depression and anxiety.8 The weight of evi-
dence suggests that small molecule antagonists of the MCH1
receptor could be useful in the treatment of obesity or mood disor-
ders. The promising in vitro and in vivo pharmacology of published
MCHR1 antagonists has solidified the MCH1 receptor as an attrac-
tive target for a number of potential disease indications.9
In an effort to discover potent MCHR1 antagonists, we identified
indolyl azetidines, exemplified by compound 1 (Fig. 1), which have
good in vitro properties and are effectively devoid of hERG channel
affinity issues.10 Compound 1, however, exhibits poor CNS penetra-
tion apparently due to facile Pgp efflux. Herein, we describe our
lead optimization efforts, focused on mitigating the Pgp efflux,
with indolyl azetidine and dihydroindolyl azetidine rMCHR1
antagonists.
In order to monitor the efflux properties of the compounds, we
conducted an MDR1-MDCK11 permeability experiment with com-
pound 1 to investigate its Pgp liability (Fig. 2). The apparent per-
meability measured bi-directionally, after 2 h incubation, was
0.19 ꢀ 10ꢁ6 cm/s (PappA-to-B) and 26.3 ꢀ 10ꢁ6 cm/s (PappB-to-A).
This resultant high efflux ratio (144) with good recovery, 72%
N
O
rMCHr1, Ki = 11 nM
N
H
hERG IC50 = 12 µM
N
O
1
⇑
Corresponding author. Tel.: +1 201 350 0152; fax: +1 201 261 0623.
E-mail address: sph@lundbeck.com (S.-P. Hong).
Figure 1. Profile of rMCHR1 antagonist 1.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.07.020

K. Lu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5310–5314
5311
Figure 2. MDR1-MDCK profile and B/P ratio in +/ꢁPgp mice after iv administration of compound 1.
(A-to-B) and 71% (B-to-A), respectively, portrays the apparent
affinity for the Pgp transporter system. Furthermore, in the Pgp
KO mice, a 6–8 h window is required to reach high brain levels sug-
gesting the compound also has relatively poor intrinsic permeabil-
ity which may confound the Pgp efflux data.12 Supporting this
hypothesis, the brain to plasma ratio, after a 15 mg/kg iv dose,
was substantially improved (B/P = 2.7) over 8 h in Pgp knock-out
mice relative to a low brain to plasma ratio (B/P = 0.3) in wild types
(see Supplementary data). The almost 10-fold improvement in B/P
ratio in Pgp KO mice (B/P = 2.7 vs wild type) underscores the strong
Pgp substrate affinity of compound 1.
Recently, a rule of 4 has been formulated to predict relative pro-
pensity for Pgp efflux liability.13 Compounds with a molecular
weight <400, containing a total number of nitrogen and oxygen
atoms <4, and a basic pKa14 <8 are unlikely to be Pgp substrates.
The presence of hydrogen bond donors is also deemed to be detri-
mental. Compound 1 has a low molecular weight (385), but a high
heteroatom count (N + O = 5), relatively high basicity (pKa = 8.7),
one hydrogen bond donor, and five rotatable bonds. Not surpris-
ingly, this indicates a reasonable chance of Pgp liability, as is borne
out by the experimental data. We logically envisioned a design
strategy focused on lowering the pKa, reducing the number of het-
ero atoms in the molecule, removing the hydrogen bond donor and
changing the overall conformational mobility to mitigate Pgp
efflux.
The synthesis of the indolyl azetidine derivatives prepared to
investigate optimization of these properties (1 and 5a–f) is out-
lined in Scheme 1. Indolyl-hydroxyazetidine 3 was readily ob-
tained via a coupling reaction between 6-bromo-indole (2) and
N-Boc-azetidin-2-one in the presence of potassium hydroxide in
refluxing methanol. Subsequent LiAlH4 reduction of intermediate
3 in refluxing THF resulted in selective dehydroxylation and con-
comitant reduction of the Boc group to afford intermediate 4a in
31% overall yield. Surprisingly the bromine functionality in the
molecule remained intact under reductive conditions, presumably
due to the electron rich environment of the indole. Selective dehy-
droxylation of intermediate 3 could be achieved without Boc re-
moval with a 3:1 mixture of Et3SiH/TFA15 in DCM at 0 °C to
afford 1-N-Boc-indolylazetidine 4b in good yield. Subsequent cop-
per mediated coupling reactions between bromoindolyl-azetidines
4a–c and the corresponding pyridones16 were carried out to afford
compounds 1 and 5a–f in good yields (78–92%). The couplings
were achieved by heating a mixture of CuI (0.5–1.0 equiv), trans-
N,N0-dimethyl-cyclohexane-1,2-diamine (1.0 equiv) and K2CO3
(1.5–2.0 equiv) in DMF at 100 °C for 16 h. The substituents R3 for
compound 5d–f were installed before coupling using the corre-
sponding alkyl halides (MeI, 2-fluoroethyl bromide or 2-methoxy-
ethyl bromide) in the presence of base in DMF. The methyl
substituent at R2 of compounds 4c and 5c was installed with stan-
dard alkylation conditions (KOtBu, MeI in THF) in quantitative
yield.
In general, it was found that the indolyl azetidine derivatives 1
and 5a–f have good binding affinity for the rMCH1 receptor. (Table
1) This series of analogs tolerates a variety of substituents at the R1,
R2 and R3 positions. Interestingly, shorter and rigid ligands such as
phenylpyridones (5b and f) still maintain good rMCHR1 binding
affinity. The hydrogen bond donor is not essential for binding affin-
ity as capping the indole NH with a methyl substituent (5c and f)
resulted in similar binding affinities. The flexibility of binding po-
tency in this template allowed us to investigate several different
approaches to potentially mitigate the Pgp liability. First, we tried
to modulate the hydrogen bond acceptor capacity of the benzyloxy
pyridone moiety by adding halogen substituents. The simple addi-
tion of a fluorine substituent at the benzyloxy terminus of R1 (5a)
slightly increased brain exposure, but the efflux ratio remained
high (150).17 Several other attempts to mitigate Pgp efflux by add-
ing halogen atoms such as F or Cl at C3 of the pyridone ring or C5 of
the indole core moiety were unsuccessful. Next, we turned our
attention to lowering the basicity of the template. Installation of
a methoxyethyl substituent at R3 (5d) slightly lowered basicity
(pKa = 8.2) with a concomitant improvement in brain exposure.
However, the efflux ratio (MDR1-MDCK = 88) remained high. Fur-
ther lowering the basicity (pKa = 6.9) by placing a strong electron
withdrawing fluoroethyl substituent18 at R3 (5e) increased brain
exposure further without measurably improving the efflux liability
(ratio = 43). We also believed the flexible pyridone moiety played a
role in poor CNS penetration by allowing the molecule to accom-
modate
a reasonable Pgp binding conformation. Under this
hypothesis, the conformational flexibility of the molecule was re-
duced by eliminating the hydroxymethyl linker (5b). This modifi-
cation, to our surprise, retained MCH potency, but resulted in
improved total brain exposure. Furthermore, capping the hydrogen
bond donor alone by methylation of indole NH (5c) did not appear
to resolve the Pgp efflux based on a maintained poor B/P ratio
(0.03). We then decided to apply a combined approach of confor-
mational restraint; capping the hydrogen bond donor (indole
NH); and attenuation of the basicity (pKa = 7.4). This combined ap-
proach (compound 5f) resulted in high total brain exposure with a

5312
K. Lu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5310–5314
N
Boc
N
N
b
a
HO
O
f
N
H
Br
N
N
R2
N
H
Br
N
H
R1
Br
2
3
4a
1, R1 = PhCH2O, R2 = H
5a, R1 = 2-F-PhCH2O, R2 = H
g
, R = 4-Cl-Ph, R2 = H
1
5b
5c
, R1 = PhCH2O, R2 = Me
c
R3
Boc
N
N
d, e, f
O
N
N
N
R
R2
Br
g
R1
5d, R1 = PhCH2O, R2 = H, R3= MeO(CH2)2
5e, R1 = PhCH2O, R2 = H, R3 = F-(CH2)2
4b, R = H
, R = Me
4c
, R1 = 4-F-Ph, R2 = Me, R3 = F-(CH2)2
5f
Scheme 1. Synthesis of indolyl azetidine derivatives. Reagents and conditions: (a) N-Boc-azetidin-2-one, KOH, MeOH, reflux, 41%; (b) LiAlH4, THF, reflux, 76%; (c) Et3SiH/TFA
(3:1), DCM, 0 °C, quant; (d) TFA/DCM, quant (crude); (e) K2CO3, R3-halides, DMF, 20–40%; (f) pyridones,16 CuI, trans-N,N0-dimethyl-cyclohexane-1,2-diamine, K2CO3, DMF,
100 °C, 78–92%; and (g) KOtBu, 18-C-6, MeI, THF, quant.
Table 1
rMCHR1 binding affinity of indolyl azetidine derivatives, their B/P exposure, and MDR1-MDCK efflux ratios
R3
N
O
N
N
R2
R1
R1
R2
R3
pKa
rMCH1, Ki (nM)
Brain (ng/g)b
Plasma (ng/mL)b
PappA-to-B (ꢀ10ꢁ6 cm/s)
PappB-to-A (ꢀ10ꢁ6 cm/s)
Effluxd
a
No.
1
PhCH2O
2-F–PhCH2O
4-Cl–Ph
PhCH2O
PhCH2O
PhCH2O
4-F–Ph
H
H
H
Me
H
Me
Me
Me
Me
MeO(CH2)2
F-(CH2)2
F–(CH2)2
8.7
8.7
8.7
8.8
8.2
6.9
7.4
11
11
22
48
0.2
0.2
0.9
—
0.4
1.4
7.1
26.3
25.3
53.7
—
34.1
58.9
45.4
144
150
60
—
88
5a
5b
5c
5d
5e
5f
6.7
7.8
11
5.2
4.3
9.0
140
350
4000c
310
620
1000
100
110c
49
130
810
H
Me
43
6.4
a
b
c
Calculated base pKa.
Rat PK at 10 mg/kg, PO, 4 h.
Rat PK at 10 mg/kg, SC, 4 h.
d
MDR1-MDCK efflux ratio (PappB-to-A/PappA-to-B).
significant improvement in B/P ratio (0.8) and markedly lower ef-
flux (PappB-to-A/PappA-to-B = 6.4). However, the efflux ratio,
although improved, still needed to be optimized to further mitigate
the Pgp liability. The persistent Pgp efflux with indolyl azetidine
derivatives, in light of the progress, inspired us to modify the in-
The synthesis of dihydroindolyl azetidine derivatives (9a–e) is
outlined in Scheme 2. Reductive amination of commercially avail-
able 6-bromo-dihydroindole 6 and N-Boc-azetidine-2-one readily
afforded 7 in good yield. The copper catalyzed coupling of 6-bro-
modihydroindole azetidine 7 with the corresponding pyridones
gave 8. Subsequent Boc deprotection and reductive amination
(R2 = Me) or alkylation (R2 = F-ethyl) resulted in dihydroindolyl
azetidine derivatives 9b–e. Alternatively, 9b–e were synthesized
dole core itself to achieve our goals. We envisioned
a
dihydroindole, which has similar overall topology, but no hydrogen
bond donor, thus potentially reducing the Pgp affinity further.

K. Lu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5310–5314
5313
Boc
N
R2
N
Boc
N
H
N
N
O
N
c
b
O
a
N
N
Br
N
Br
R1
6
R1
7
8
1
2
9a
9b
9c
, R = PhCH2O, R = H
c, b
1
2
, R = PhCH2O, R = Me
1
2
, R = PhCH2O, R = F-(CH2)2
9d, R1 = 4-Cl-Ph, R2 = Me
9b-e
9e, R1 = 4-Cl-Ph, R2 = F-(CH2)2
Scheme 2. Synthesis of dihydroindolyl azetidine derivatives. Reagents and conditions: (a) N-Boc-azetidin-2-one, NaBH(OAc)3, DCM, 93%; (b) pyridones,16 CuI, trans-N,N0-
dimethyl-cyclohexane-1,2-diamine, K2CO3, DMF, 100 °C, quant (crude); and (c) TFA, DCM; then formaldehyde, NaBH(OAc)3, DCM (or) 2-fluoroethyl bromide, K2CO3, DMF, 14–
31% (for two steps).
Table 2
rMCHR1 binding affinity of dihydroindolyl azetidine derivatives, their B/P exposure, and MDR1-MDCK efflux ratios
R2
N
N
O
N
R1
a
No.
R1
R2
pKa
rMCH 1, Ki (nM)
Brain (ng/g)b
Plasma (ng/mL)b
PappA-to-B (ꢀ10ꢁ6 cm/s)
PappB-to-A (ꢀ10ꢁ6 cm/s)
Effluxc
9a
9b
9c
9d
9e
PhCH2O
PhCH2O
PhCH2O
4-Cl–Ph
4-Cl–Ph
H
Me
F–(CH2)2
Me
F–(CH2)2
10.4
8.6
6.9
8.6
6.9
2.4
2.5
4.9
4.9
6.5
27
130
500
420
190
650
—
—
—
780
520
600
1100
2.6
17.7
—
36.5
38.2
—
14
2.2
—
28.9
30.1
1
a
b
c
Calculated base pKa.
Rat PK at 10 mg/kg, PO, 4 h.
MDR1-MDCK efflux ratio (PappB-to-A/PappA-to-B).
by the reverse synthetic sequence (i.e., Boc deprotection, alkylation
or reductive amination, and then copper catalyzed coupling).
To our satisfaction, the dihydroindolyl azetidine analogs 9a–e
(Table 2) have similarly potent rMCHR1 antagonist binding affini-
ties to the indolyl azetidine derivatives (1 and 5a–f). The benzyloxy
analog 9a, unsubstituted at the azetidine terminus shows a low to-
tal brain exposure presumably due to high basicity (pKa = 10.4). A
methyl substituent at R2 of the azetidine (9b) attenuates basicity
(pKa = 8.6) significantly versus compound 9a and thus the total
brain exposure of compound 9b is substantially improved. How-
ever, the efflux is still somewhat high (ratio = 14). We further low-
ered the basicity by installing a 2-fluoroethyl group at R2 (9c,
pKa = 6.9). The Pgp efflux (ratio = 2.2) of compound 9c was signifi-
cantly improved and now deemed acceptable. However, to our dis-
may, the total brain exposure of compound 9c is lower than that of
compound 9b, presumably due to an increase in lipophilicity
(c log D7.4 = 4.4 vs 3.1, respectively) and rotatable bonds (5 vs 7,
respectively). Subsequent limiting of conformational flexibility by
installing a 4-chlorophenyl at R1 resulted in good brain exposure
(9d, B/P >3). Further lowering the basicity (pKa = 6.9) with a 2-flu-
oroethyl substituent at R2, as before, improved brain exposure
additionally (9e). The MDR1-MDCK data (PappB-to-A/PappA-to-
B = 1) of compound 9e suggests it will be effectively devoid of a
Pgp efflux. Compound 9e was subsequently advanced in our inves-
tigation of MCHR1 ligands, due to good rMCHR1 binding affinity,
high brain exposure and apparent lack of a Pgp efflux, the results
of which will be reported in due course.
In summary, we have described our lead optimization efforts to
identify the potent rMCHR1 antagonist 9e with apparent lack of
Pgp efflux liability. The combined strategies to solve the Pgp efflux
issue involved lowering the basicity, reducing conformational flex-
ibility, reducing heteroatom count, and removing a hydrogen bond
donor. This optimally engineered derivative maintained good bind-
ing affinity against rMCH1 receptor with excellent CNS exposure,
allowing us to examine the utility of MCHR1 antagonists as
potential CNS therapeutics.
Acknowledgments
The authors would like to thank Arifa Husain, Christine
G. Mazza, Lingyun Wu, Mohammad R. Marzabadi and Marc Labelle
for their helpful discussion within the team. We also thank Asanthi

5314
K. Lu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5310–5314
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.07.020.
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