Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part II

Article abstract of DOI:10.1016/j.bmcl.2014.06.028

We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identif

Full text of DOI:10.1016/j.bmcl.2014.06.028

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3238–3242
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and pharmacological evaluation of novel polycyclic
heteroarene ethers as PDE10A inhibitors: Part II
Sanjib Das, Dnyaneshwar E. Shelke, Rajendra L. Harde, Vijayshree B. Avhad, Neelima Khairatkar-Joshi,
Srinivas Gullapalli, Praveen K. Gupta, Maulik N. Gandhi, Deepak K. Bhateja, Malini Bajpai,
Ashwini A. Joshi, Megha Y. Marathe, Girish S. Gudi, Satyawan B. Jadhav, Mahamad Yunnus A. Mahat,
⇑
Abraham Thomas
Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as
PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimiza-
tion of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-
2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent
selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited
high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excel-
lent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly
schizophrenia.
Received 3 March 2014
Revised 3 June 2014
Accepted 10 June 2014
Available online 19 June 2014
Keywords:
Pyrrolo[3,2-b]quinoline
Pyrrolo[3,2-b]pyridine
CAR model in SD rats
PPI deficit model
Ó 2014 Elsevier Ltd. All rights reserved.
Sniffing versus climbing in mice
Schizophrenia is a debilitating neuropsychiatric disorder con-
sisting of positive or psychotic symptoms (bizarre delusions, hallu-
cinations and paranoia), negative symptoms (lack of motivation
and social withdrawal) and cognitive deficits (impaired executive
functioning).1 The currently available typical-(D2 receptor antago-
nists) and atypical antipsychotics (D2 and 5HT2a antagonists) are
effective in treating only positive symptoms. These drugs are inef-
fective against negative symptoms and cognitive deficits of schizo-
phrenia and are associated with undesired motor side effects,
weight gain, diabetes and QT prolongation.2 There is a high unmet
need for new therapeutics that can address negative and cognitive
symptoms along with good efficacy in treating positive symptoms
of the disease with fewer side effects. Preclinical studies suggest
that inhibition of PDE10A enzymatic activity can provide antipsy-
chotic, pro-cognitive, negative symptom efficacy and an atypical
anti-schizophrenic profile with improved safety.3,4
initiated phase 2 clinical trials of OMS824 for treating positive
and negative symptoms associated with schizophrenia and
Huntington’s disease, and has received fast track designation from
US FDA. Using an analogue-based design, we had reported novel
pharmacophoric scaffolds having good PDE10A inhibitory activity.7
Compound 1 (Fig. 1) from the above report inhibited PDE10A with
an IC50 value of 123.2 nM.7 The compound suffered from
exhaustive metabolism with 0.2% and 0.1% remaining after 1.0 h
incubation in the rat and human liver microsomes, respectively.
This instability has mainly been attributed to the presence of
N
N
N
N
N
N
N
N
O
O
Me
N
Me
N
Several companies with prospective programs have reported
large numbers of small molecule PDE10A inhibitors.5 Pfizer’s
well-studied molecule MP-10 (PF-02545920) failed to achieve pri-
mary efficacy endpoints in schizophrenia trials and the molecule is
now being re-evaluated for Huntington’s disease.6 Omeros has
N
N
9d
1
hIC50: 123.2 nM
rLM: 0.2%
hIC50: 19.1 nM
rLM: 83.1%
hLM: 85.2%
hLM: 0.1%
⇑
Corresponding author. Tel.: +91 22 6772 0000; fax: +91 22 2778 1206.
E-mail address: abraham_thomas@glenmarkpharma.com (A. Thomas).
Figure 1. Comparison of PDE10A inhibitors 1 and 9d.
http://dx.doi.org/10.1016/j.bmcl.2014.06.028
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

S. Das et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3238–3242
3239
metabolically liable ethoxy ether linker as identified by our metab-
olite identification (Met-ID) studies.7
N
Cl
OH
THPO
CHO
b
NH2
7
a
The problem of low metabolic stability was successfully
resolved by replacing the ethoxy ether linker with phenoxy ether
as in the case of compound 9d (Fig. 1), that resulted in high micro-
somal stability (83.1% and 85.2%) and 6-fold improvement in
potency to 19.1 nM. This lead compound was further optimized
to improve potency, selectivity and physicochemical properties
and the results are described in this Letter.
2
N
N
R
N
Me
N
O
8
Me
N
N
c
N
O
In our previous communication (Part 1), we had extensively
studied SAR of tricyclic PDE10A inhibitors based on pyrrolo[3,2-
b]quinolines and pyrido[2,3-b]indoles.7 Based on the SAR data we
focused on selected linker-modified derivatives of pyrrolo[3,2-
b]quinolines as shown in Schemes 1 and 2. The approach employed
for the synthesis of pyrrolo[3,2-b]quinoline linked compounds of
the formula 5a–e and 6 is outlined in Scheme 1. Condensation
reaction of 2-chloroquinolin-3-amine 28 with THP protected
2-(3-hydroxyphenyl)acetaldehyde 39 gave 1H-pyrrolo[3,2-b]quin-
oline,10 which on N-methylation followed by deprotection of THP
group afforded the desired 3-substituted phenol derivative 4. The
coupling reaction of 4 with appropriately substituted 2-chloropyr-
imidine gave aryl ethers 5a–e in 55–80% yield. Similarly, 4 was
coupled with 5-(3-chloropyrazin-2-yl)pyrimidine to give 6 in 62%
yield.
The inhibitory activity of compounds was measured using a
scintillation proximity assay with [3H]-cAMP as the substrate and
by measuring hydrolysis of cAMP to AMP using recombinant
human PDE10A enzyme and the results are shown in Table 1.11
From amongst the 1,3-disubstituted pyrimidine derivatives 5a–e,
compound 5a bearing a pyrazole ring at the 3-position showed
good PDE10A inhibition with a potency of 20.9 nM. The fluoro-
phenyl derivative 5b and the methoxyphenyl derivative 5c showed
nearly 5-fold loss in potency. Compounds 5d and 5e with pyrimi-
dine and morpholine substituent at 3-position showed a potency
of 18.2 and 29.2 nM, respectively. However, compound 6 with a
1,2-substitution around the central pyrazine core resulted in poor
potency.
Me
N
N
9a
, R = 4-fluorophenyl
N
9b, R = 4-methoxyphenyl
N
N
9c
, R = pyridin-4-yl
9d, R = pyrimidin-5-yl
10
Scheme 2. Reagents and condition: (a) (i) (t-Bu)3P.HBF4, Pd2(dba)3, KOAc, DMA,
120 °C, N2, 16 h, 37%, (ii) CH3I, NaH, DMF, 0 °C to rt, 1 h, 82%, (iii) Concd HCl, MeOH,
THF, 0 °C, 30 min, 62%; (b) 3-substituted-2-chloropyrazines, Cs2CO3, DMSO, 80 °C,
12 h, 48–75%; (c) 2-chloro-4,50-bipyrimidine, Cs2CO3, DMSO, 80 °C; 10 h, 52%.
the THP group afforded the desired 4-substituted phenol derivative
8. The coupling reaction of 8 with appropriate 2-chloro-3-substi-
tuted pyrazine gave 9a–d in 48–75% yield. Similarly, coupling reac-
tion of 8 with 2-chloro-4,50-bipyrimidine furnished 10 in moderate
yield.
The 1,2-disubstituted pyrazine derivatives 9a and 9b with aryl
substitution resulted in moderate potency of 177.2 and
153.1 nM, respectively. Introduction of a pyridine ring as in the
case of 9c and a pyrimidine ring as in the case of 9d resulted in
excellent potency of 8.5 and 19.1 nM, respectively. Compound 10
with a 1,3-substitution pattern around the central pyrimidine ring
resulted in moderate PDE10A potency (entry 11).
In order to understand the minimum structural requirement for
good PDE10A inhibition, we considered the replacement of the
tricyclic pyrrolo[3,2-b]quinoline moiety with the bicyclic pyrrolo
[3,2-b]pyridine in selected derivatives. The approach employed
for the synthesis of these compounds is depicted in Scheme 3. N-
methylation of 3-bromopyrrolo[3,2-b]pyridine 11a–c with methyl
iodide followed by Suzuki coupling with 4-hydroxyphenylboronic
acid gave the 4-hydroxyphenyl derivative 12a–c. Phenol deriva-
tives 12a and 12c were coupled with 2-chloro-3-(pyridin-4-yl)pyr-
azine to furnish the corresponding phenyl ethers 13a and 13b in
The synthesis of isomeric 4-substituted phenol derivative 8 and
its use in the synthesis of compounds 9a–d and 10 is shown in
Scheme 2. As described above, condensation of 2 with THP
protected 2-(4-hydroxyphenyl)acetaldehyde 79 gave 1H-pyrrol-
o[3,2-b]quinoline, which on N-methylation and deprotection of
OH
OH
CHO
N
Cl
THPO
N
Br
N
3
a
HO
N
B(OH)2
c
NH2
N
N
N
R
Me
N
2
4
H
a
N
R
11a, R = H
b
c
Me
12a, R = H
11b
N
, R = CH3
R
N
11c, R = Cl
12b
, R = CH3
N
N
N
12c, R = Cl
Me
N
O
O
b
N
O
N
Me
Me
N
N
N
N
O
N
N
N
5a, R = pyrazol-4-yl
Me
N
5b
, R = 4-fluorophenyl
R
5c, R = 4-methoxyphenyl
N
14a, R = H
5d
, R = pyrimidin-5-yl
6
14b
, R = CH3
13a
13b, R = Cl
5e, R = morpholin-1-yl
, R = H
R
14c, R = Cl
Scheme 1. Reagents and conditions: (a) (i) (t-Bu)3P.HBF4, Pd2(dba)3, KOAc, DMA,
120 °C, N2, 16 h, 44%, (ii) CH3I, NaH, DMF, 0 °C to rt, 1 h, 80%, (iii) Concd HCl, MeOH,
THF, 0 °C, 30 min, 65%; (b) 3-substituted 2-chloropyrimidines, Cs2CO3, DMSO, 80 °C,
12–16 h, 55–80%; (c) 5-(3-chloropyrazin-2-yl)pyrimidine, Cs2CO3, DMSO, 80 °C,
16 h, 62%.
Scheme 3. Reagents and conditions: (a) (i) CH3I, NaH, DMF, 0 °C to rt, 1 h, 66–85%,
(ii) 4-hydroxyphenylboronic acid, Pd(PPh3)4, K2CO3, DMF, water, 80 °C, N2, 12–16 h,
52–80%; (b) 2-chloro-3-(pyridin-4-yl)pyrazine, Cs2CO3, DMSO, 80 °C, 10 h, 58–70%,
(c) 2-fluoro-3,40-bipyridine, Cs2CO3, DMSO, 80 °C, 12 h, 55–65%.

3240
S. Das et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3238–3242
58% and 70% yield, respectively. Similarly, phenols 12a–c were
coupled with 2-fluoro-3,40-bipyridine to give the desired com-
pounds 14a–c.
OH
OH
N
b
a
N
N
The compound 13a bearing a bicyclic pyrrolo[3,2-b]pyridine
core resulted in single digit potency of 6.3 nM. However, the corre-
sponding chloro derivative 13b showed 11-fold loss in potency.
The compounds 14a–c with the central pyridine core were more
potent than the pyrazine derivatives 13a–b as shown in Table 1.
Having accomplished good in-vitro potency with the bicyclic
systems, we turned our attention towards the synthesis of the
more flexible cyclohexene derivative 18 and cyclohexane deriva-
tive 19 as shown in Scheme 4. Condensation reaction of 1H-pyrrol-
o[3,2-b]pyridine 15 with 1,4-dioxaspiro[4,5]-decan-8-one in the
presence of KOH followed by N-methylation, deprotection of
1,3-dioxolane moiety and finally carbonyl group reduction resulted
in cyclohexenol 16.12 The alcohol 16 on reaction with 3-(pyrimi-
din-5-yl)pyrazin-2-ol under Mitsunobu reaction conditions affor-
ded 18 in good yield. Similarly, the saturated alcohol 1713
obtained by double bond saturation of 16 on Mitsunobu reaction
with 3-(pyrimidin-5-yl)pyrazin-2-ol gave 19.
N
H
N
N
Me
Me
15
16
17
c
c
N
N
N
N
N
N
N
O
O
Me
Me
N
N
N
N
N
19
18
Scheme 4. Reagents and conditions: (a) (i) 1,4-dioxaspiro[4.5]decan-8-one, KOH,
MeOH, reflux, 16 h, 84%, (ii) CH3I, NaH, DMF, 0 °C to rt, 1 h, 82%, (iii) 1 N HCl, THF,
rt—reflux, 2 h, 91%, (iv) NaBH4, MeOH, 0 °C, 30 min, 93%; (b) Pd-C, EtOH, H2, rt, 2 h,
87%; (c) 3-(pyrimidin-5-yl)pyrazin-2-ol, DEAD, PPh3, THF, 0 °C to rt, 10 h, 53–58%.
The non-planar cyclohexene derivative 18 showed substantial
loss in potency (IC50: 135.5 nM) compared to the aromatic deriva-
tives (cf. Scheme 3), suggesting that flat molecules are ideal as
PDE10A inhibitors.14 The effect is more pronounced in the fully sat-
urated derivative 19, which showed an IC50 value of 552 nM (entry
18).
extent of disappearance of compounds in liver microsomal incuba-
tions at 37 °C for 60 min. The pyrimidine derivatives 5a and 5d
showed moderate to poor stability, while 5e showed poor stability
across species suggesting that the morpholine ring is highly sus-
ceptible to oxidative metabolism.15 The pyrazine derivatives 9c
and 9d showed good stability across species. Compounds 13a–b
and 14a–c based on the bicyclic core retained good metabolic sta-
bility across species. As expected, the metabolically more labile
cyclohexene derivative 18 was less stable than the corresponding
fully saturated analogue 19.
Having achieved good potency, selectivity and in-vitro meta-
bolic stability for several compounds (see Tables 1–3), we decided
to study 13a as a tool compound in in vivo efficacy models. From
the overall profile of bicyclic compounds, 13a and 14c appear to
be the best among all compounds studied. The calculated physico-
chemical properties of 13a (Mol. Wt.: 379.4; cLogP: 3.2; tPSA:
61.9) were found to be superior to 14c (Mol. Wt.: 412.8; cLogP:
4.7; tPSA: 49.5) and therefore 13a was selected for further profil-
ing. In a non-cell based PAMPA permeability assay, compound
13a was found to be highly permeable (Papp: 2.97 ꢁ 10ꢀ6 cm/s).
The pharmacokinetic (PK) profile of 13a was studied upon oral
administration in male Swiss albino mice and male SD rats. Oral
As a part of the lead optimization strategy, selected potent com-
pounds listed in Table 1 were screened against a broader panel of
PDEs and the results are shown in Table 2. The PDE selectivity
assay of compounds 5a, 5d–e, 9c–d, 13a–b and 14a–c was carried
out using human recombinant PDEs 2ꢀ5, 7 and 11. The percentage
inhibition of PDEs was measured at 1.0 and 10.0 lM concentra-
tions of the compounds.11 The compounds, in general, are highly
selective over all other PDEs except in the case of 5e, as it showed
substantial inhibition of PDE11 at both 1.0 and 10.0
tions. The compounds 13a and 13b showed poor inhibition at both
1.0 and 10 M concentrations for all related PDEs studied and are
lM concentra-
l
therefore most selective among the compounds studied.
Selected compounds were then subjected to in vitro metabolic
stability studies using the male Wistar rat, male CD1 mouse, male
Beagle dog, male cynomolgus monkey and pooled human liver
microsomes and the results are shown in Table 3. The in vitro met-
abolic stability of compounds was determined by measuring the
Table 1
SAR of compounds 5a–e, 6, 9a–d, 10, 13a–b, 14a–c, 18–19
Entry
Compd
% Inhib. (1.0
l
M)b
hIC50 (nM)a
rIC50 (nM)a
mIC50 (nM)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
5a
5b
5c
5d
5e
6
9a
9b
9c
9d
10
13a
13b
14a
14b
14c
18
89.3
76.3
72.4
95.0
93.1
76.3
76.9
72.3
97.2
94.8
85.3
98.0
79.7
98.0
98.3
95.4
78.0
68.9
20.9 2.9
115.7 7.5
102.6 3.9
18.2 1.7
29.2 2.2
266.7 11.2
177.2 21.3
153.1 5.8
8.54 1.2
19.1 1.2
128.1 12.6
6.3 0.5
71.0 7.8
1.3 0.2
0.3 0.1
2.6 0.3
135.5 14.1
552.1 52.1
122.4 38.3
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
22.6 0.4
ND
ND
11.7 0.7
ND
4.1 0.1
1.2 0.03
6.7 0.1
ND
90.3 7.8
166.9 19.5
1450 135.7
ND
132.2 8.2
29.4 3.1
31.1 2.3
ND
16.1 2.1
141.4 21.7
5.8 0.9
0.8 0.1
7.1 0.8
552.2 27.1
371.7 2.5
19
ND
a
IC50 values are mean SD of two independent experiments using 7 to 9-point concentration-response curve. ND refers to ‘not determined’.
Percentage inhibition values are for human PDE10A enzyme.
b

S. Das et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3238–3242
3241
Table 2
PDE selectivity data for 5a, 5d–e, 9c, 9d, 13a–b, 14a–ca
Compd
Percentage inhibition at 1.0 and 10.0 l
M concentrationa
hPDE2
hPDE3
hPDE4
hPDE5
hPDE7
hPDE11
5a
5d
5e
9c
16.1/40.8
11.4/38.5
15.7/76.2
5.3/34.1
8.9/14.2
3.3/42.4
11.3/16.1
16.6/69.6
24.9/43.0
12.3/12.6
4.5/27.5
1.1/4.8
0.3/21.5
0.8/2.5
0.3/9.4
0.0/6.3
0.7/9.8
0.1/7.4
0.9/6.4
0.0/0.0
7.9/34.7
4.2/57.0
5.6/1.0
8.2/19.0
1.5/23.6
16.0/33.3
9.4/19.3
9.4/17.3
0.8/21.6
0.1/19.3
2.2/23.2
9.6/16.7
2.4/3.1
16.7/27.2
4.5/14.0
5.8/19.5
4.0/15.8
6.0/20.2
2.5/44.5
5.9/53.1
5.0/39.9
3.7/28.3
10.5/17.5
27.3/38.5
24.4/43.8
44.6/76.3
0.8/6.8
3.3/21.8
4.9/11.2
3.1/5.7
3.0/29.0
0.1/8.3
8.5/3.0
0.0/7.6
9d
1.3/19.5
0.0/33.8
4.1/25.4
0.9/18.0
0.0/10.8
3.5/6.9
13a
13b
14a
14b
14c
a
Percentage inhibition (1.0/10 lM) values are mean of two independent experiments run in duplicate for both concentrations.
Table 3
Metabolic stability of 5a, 5d–e, 9c–d, 13a–b, 14a–c, 18 and 19a
correlation between in-vitro potency, pharmacokinetics (PK) and
pharmacodynamics (PD), compound 13a was screened against rats
and mice PDE10A enzyme. It showed an IC50 of 16.1 nM in rats and
11.7 nM in mice, which is close to the human potency of 6.3 nM.
First, the compound 13a was evaluated in reversal of MK-801
(dizocilpine)-induced hyperactivity in SD rats and the results are
shown in Figure 2.16 The compound 13a upon oral dosing at 1.0,
3.0 and 10.0 mg/kg in female rats produced significant dose-
dependent efficacy on locomotion, stereotypy and ataxia parame-
ters, demonstrating the ability of 13a to alleviate glutamatergic
dysfunction.3 It showed an ED50 of 1.63 mg/kg on locomotor
activity with a superior efficacy profile on all parameters when
compared to the standard PDE10A inhibitor MP-10 (see
Supplementary data).
The compound 13a was then evaluated in the conditioned
avoidance response (CAR) model in SD rats as shown in Figure 3.3,17
The compound upon oral dosing at 1.0, 2.5 and 10.0 mg/kg pro-
duced significant dose-dependent efficacy in the CAR model of psy-
chosis with an ED50 of 2.08 mg/kg on disruption of avoidance
response. There was a good correlation between inhibition of
Compd
Rat
Mouse
Dog
Monkey
Human
5a
5d
5e
17.3
44.7
0.4
60.4
3.9
0.6
52.0
40.3
1.3
38.1
4.5
0.6
75.4
39.8
8.2
9c
9d
75.0
83.1
51.0
68.0
38.4
46.2
64.0
5.9
75.1
76.1
46.2
70.5
40.2
48.1
67.1
8.5
92.0
77.0
65.8
55.3
39.7
32.3
54.7
43.3
68.6
71.0
68.3
70.5
40.7
39.8
13.7
54.5
0.0
96.0
85.2
77.4
77.0
59.6
62.5
80.9
12.2
48.8
13a
13b
14a
14b
14c
18
19
72.5
50.3
0.0
a
Values are mean of three independent experiments.
administration of 13a as methyl cellulose suspension in mice and
rats at 10 mg/kg dose resulted in very good plasma concentrations
and exposures as shown in Table 4. The systemic exposures of 13a
in SD rats were found to be around 13 fold higher than in Swiss
albino mice. The significantly higher systemic clearance could be
one of the major reasons for relatively poor oral PK in Swiss albino
mice as compared to SD rats. The plasma clearance of 13a after
intravenous administration in Swiss albino mice was found to be
significantly higher as compared to that in rats (68.4 mL/min/kg
vs 1.6 mL/min/kg). Because of this higher systemic clearance of
13a in mice, the relative oral bioavailability in mice was found to
be only 8% to that in rats.
In a separate experiment, the concentrations of 13a were mea-
sured in brain tissue upon oral administration in male SD rats.
Further, the calculated total brain concentrations were converted
to free brain concentrations using unbound fraction in brain deter-
mined in an in-vitro brain homogenate binding assay. The calcu-
lated free concentrations of 13a in the brain at 1.0 h post-dose
were at par with in vitro IC50 value and found to be in the range
of 5–13 nM.
Sham
Vehicle
75
60
45
30
15
0
MP-10 3 mg/kg, i.p.
Compound 13a 1 mg/kg, p.o.
27%
***
Compound 13a 3 mg/kg, p.o.
Compound 13a 10 mg/kg p.o.
74%
***
18%
32%
**
80%
***
90%
***
59%
59%
***
*** 86%
95%
96%
*** ***
99%
***
***
-15
Locomotion
Stereotypy
Ataxia
Figure 2. Effect of compound 13a on MK-801- induced psychotic behavioral
response in SD rats. ⁄⁄p value <0.01; ⁄⁄⁄p value <0.001 for each dose.
We next evaluated in-vivo efficacy of 13a in four rodent models
that are predictive of anti-psychotic activity in humans. To establish
Sham
30
20
10
0
Vehicle
MP10 3 mg/kg, i.p.
17%
Compound 13a 1 mg/kg, p.o.
Compound 13a 2.5 mg/kg, p.o.
Compound 13a 10 mg/kg, p.o.
Table 4
PK profile of 13a in mice and rat at 10 mg/kg dosea
64%
***
PK parameters
Swiss Albino miceb
Sprague Dawley ratsb
90%
Cmax (ng/mL)
Tmax (h)
5490
0.5
27,642
2.0
96%
***
***
AUC0 ꢀ t (ng h/mL)
T1/2 (h)
31,563
10.4
409,855
4.4
Avoidance
Escape
Response Failure
a
Vehicle: 0.5% methyl cellulose suspension in water.
Mean of 3 animals per time point.
Figure 3. Effect of compound 13a on conditioned avoidance response (CAR) in male
SD rats, ⁄⁄⁄p value <0.001 for each dose.
b

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S. Das et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3238–3242
80
60
40
20
0
showed very good selectivity over other related PDEs and good
microsomal stability across species. The lead molecule 13a showed
excellent pharmacokinetics and ADME properties upon oral
administration. The compound showed excellent efficacy in multi-
ple antipsychotic models in rodents. The present study adds to a
growing body of evidence suggesting the potential of PDE10A
inhibitors for the management of various neuropsychiatric
disorders in humans.
Sham
***
88%
***
Vehicle
67%
**
64%
*
Risperidone 1 mg/kg, i.p.
43%
Compound 13a 1 mg/kg, p.o.
Compound 13a 3 mg/kg, p.o.
Compound 13a 10 mg/kg, p.o.
MK-801 0.09 mg/kg, s.c.
Acknowledgments
Figure 4. Effect of compound 13a in reversing the MK-801-induced prepulse
inhibition (PPI) deficit in male SD rats. ⁄p value <0.05; ⁄⁄p value <0.01; ⁄⁄⁄p value
<0.001.
We thank Ms. Aarti Sawant for her excellent technical assis-
tance in the manuscript preparation. We are also grateful to Dr.
Rajesh Diwedi and his team for analytical support for this work.
Climbing
Sniffing
-20
0
Supplementary data
20
40
60
80
100
Supplementary data (synthetic procedures, selected analytical
data, in vitro and in vivo experimental details and scanned spectra
of selected compounds) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.06.
028.
References and notes
0
15
30
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3.75
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In summary, we have demonstrated that heteroarene ether
derivatives of 1H-pyrrolo[3,2-b]quinoline and 1H-pyrrolo[3,2-
b]pyridine displayed low nanomolar potency in in vitro
radiometric PDE10A assay. Several compounds from the series
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