The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Article abstract of DOI:10.1016/j.bmcl.2012.01.113

The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3 mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.

Full text of DOI:10.1016/j.bmcl.2012.01.113

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2585–2589
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The SAR development of dihydroimidazoisoquinoline derivatives
as phosphodiesterase 10A inhibitors for the treatment of schizophrenia
⇑
,
Ginny D. Ho a, , W. Michael Seganish a, , Ana Bercovici a, Deen Tulshian a, William J. Greenlee a,
Rachel Van Rijn a, Alan Hruza b, Li Xiao b, Diane Rindgen c, Deborra Mullins d, Mario Guzzi d,
Xiaoping Zhang d, Carina Bleickardt d, Robert Hodgson d
a Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States
b Department of Structural Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States
c Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, NJ 07033, United States
d Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is
reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally
active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3 mg/kg and dis-
played a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced
hyperactivity and hypolocomotion in rats.
Received 11 December 2011
Revised 25 January 2012
Accepted 30 January 2012
Available online 9 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phosphodieasterase inhibitors
PDE10A
Schizophrenia
The phosphodiesterases (PDEs) comprise a family of widely
expressed cyclic-nucleotide hydrolyzing enzymes that hydrolyze
the 30–50 phosphodiester bond of the intracellular messenger mol-
ecules cyclic adenosine monophosphate (cAMP) and cyclic guano-
sine monophosphate (cGMP). Phosphodiesterase 10A (PDE10A) is a
dual substrate PDE that regulates both cAMP and cGMP. It is highly
expressed in medium spiny neurons of the striatum, making it an
intriguing target for the treatment of central nervous system disor-
ders. Studies employing the PDE10A inhibitors papaverine and MP-
10 in wild type and/or PDE10A knock out mice have suggested that
PDE10A inhibitors may be effective for the management of psycho-
sis in schizophrenia.1 While current antipsychotic drugs are
effective in treating positive symptoms of schizophrenia (halluci-
nations, delusions, and disorganized speech and behavior), they
are ineffective in the treatment of negative symptoms (lack of
motivation, an inability to express emotion, and apathy) and cog-
nitive dysfunction. They commonly cause extrapyramidal syn-
drome (EPS), a serious side effect characterized by a constellation
of involuntary movements. Current antipsychotic drugs are also
associated with other severe side effects including weight gain,
diabetes and QT prolongation.2–4 Therefore, a chemistry program
was initiated to identify potent, selective, and orally active PDE10A
inhibitors to evaluate the therapeutic potential.
The dihydroimidazoisoquinoline core was identified as a chem-
otype in one of our medicinal chemistry programs. Because of the
structural similarity to the literature reported PDE10 inhibitors,5,6
selected compounds were screened for PDE10A activity and iden-
tified compound 1 as a potent PDE10A inhibitor with low selectiv-
ity over PDE3A and PDE7A1 (Fig. 1). Inhibition of PDE3 and effects
on cardiovascular function has been reported in the literature.7,8
Accordingly, the selectivity over PDE3A would be an important
SAR goal. Compound 1 is a potent PDE10A inhibitor with a ligand
efficiency (LE) of 0.37. It has low plasma drug exposure in rat
MeO
MeO
O
PDE10A Ki= 8.7 nM, LE= 0.37
PDE3A Ki= 149 nM; PDE7A1 Ki= 243 nM
Other PDEs Ki > 2000 nM
N
N
S
Rat PK AUC (10 mg/kg, PO)= 0.75 µM.h
Brain concentration (6-h) < 10 ng/g (LOQ)
Monkey PK AUC (3 mg/kg, PO)= 0.17 µM.h
Heptocyte clearance: 66 µL/min/106 cells (human)
49 µL/min/106 cells (rat)
N
N
1
MW= 426.5, PSA= 69
cLogP= 2.7, cLogD= 2.7
pKa= 4.0
59 µL/min/106 cells (monkey)
hERG (IonWorks): 40% inhibition @ 10 µM
Solubility (2% DMSO @ pH= 7.4 ) > 200 µM
⇑
Corresponding author.
E-mail address: ginny.ho@merck.com (G.D. Ho).
These authors contributed equally to this work.
Figure 1. In vitro and PK profile of 1.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.113

2586
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2585–2589
MeO
MeO
3, then to isonitrile 4. An Ugi coupling smoothly provided com-
MeO
MeO
b
a
pound 5 and 6 which was in turn subjected to a Bischler–Napieral-
ski cyclization to provide dihydroimidazoisoquinoline 7 and 8. This
route provided reliable and rapid access to a range of compounds
by using different aldehydes and R1 functionality. The thiazolyl
compounds 7 and 8 could be further modified. For example, depro-
tonation with n-BuLi followed by quenching with CO2 could pro-
vide the carboxylic acid which could be converted to a variety of
amides (9)
The PDE inhibitory activity of the targeted compounds was
determined using a scintillation proximity assay with [3H]cAMP
as substrate measuring the hydrolysis of cAMP to AMP with recom-
binant human PDEs 1–11. Selected compounds were evaluated for
PK using the cassette-accelerated rapid rat screen,9 and for
anti-psychotic efficacy in the inhibition of MK-801-induced hyper-
activity assay in the rat.10 The potential for hypolocomotion was
evaluated in a spontaneous locomotor activity test11 to differenti-
ate between efficacy, as defined by reversal of the MK-801 induced
behavior, and hypolocomotoric effects of the compound.
NHCHO
NH2
NC
2
3
MeO
MeO
MeO
MeO
c
d
HN
O
4
S
NHCOR1
N
5, R1= H
6, R1= CH3
MeO
MeO
MeO
MeO
e
f
N
N
N
R1
R1
N
S
S
N
O
N
2R3RN
7, R1= H
9
8, R1= CH3
Our initial SAR development was centered on the amide modi-
fication as it was indicated from the metabolite ID data that the
amide moiety was a metabolic liability. The dimethoxy moiety
was retained in order to preserve the bidentate hydrogen bond
interaction with the protein (vide infra). Since N-demethylation
of the amide is the major metabolic pathway in the rat and mon-
key, the amides of primary amines and cyclic amines at the C-20
position of thiazole were evaluated. It appears that amides of pri-
mary amines improve the PDE3A selectivity (Table 1). The tetrahy-
dropyranyl analog 12 is the most selective target (>129-fold
against other PDE enzymes) and has an improved hepatocyte clear-
ance profile (1.4, 5.7 and 22.7 uL/min/106 cells for human, rat and
Scheme 1. Reagents and conditions: (a) HCO2Et, 70 °C, 20 h, 100%; (b) POCl3, Et3N,
THF, 89%; (c) R1CO2NH4, thiazole-5-carbaldehyde, MeOH (for 5) or CF3CH2OH (for
6), 60 °C, 4 h, 37% (5), 17% (6); (d) P2O5, MeSO3H, 75 °C, 70% (7), 32% (7); (e) (i) n-
BuLi/THF, ꢀ78 °C; (ii) CO2; (f) NR2R3, HATU, DMF.
and monkey in the PK screen,9 and high hepatocyte clearance in
human, rat, and monkey. From the in vitro metabolite identifica-
tion study conducted by incubating compound 1 with human,
rat, and monkey microsomes, it appeared that amide hydrolysis
is the major metabolic pathway in human. In the rat and monkey,
the major metabolic pathway is N-demethylation. Compound 1
was evaluated for its anti-psychotic effect in the inhibition of
MK-801-induced hyperactivity assay.10 In this study, compound
1 did not inhibited MK-801-induced hyperactivity at 30 mg/kg in
the rat dosed orally. The brain drug level at an hour after dosing
monkey) with an AUC of 0.86 lM h in the PK screen. In the in vivo
study, it is active at 30 mg/kg. The benzyl analog 13 improved
PDE3A selectivity dramatically. However, there was no plasma
drug exposure in the rat PK screen. Despite the improved potency
and/or selectivity, the low plasma exposure of these compounds
prompted further SAR optimization.
Since the amide hydrolysis is the major metabolic pathway in
the human, the des-amide analog 7 was evaluated to determine
whether the amide moiety is essential for the PDE10A inhibitory
activity. As shown in Figure 2, compound 7 is a potent PDE10A
inhibitor with a ligand efficiency of 0.46 and an improved selectiv-
ity over PDE7A1. Although it is less potent than compound 1 and
has lower plasma drug exposure in the rat PK screen, it inhibited
was 0.35 lg/g. In addition to improving the selectivity against
other PDE enzymes and enhancing the plasma and brain drug
exposure in the rat to improve the in vivo activity, the SAR devel-
opment was initiated to improve the plasma drug exposure in the
monkey since evaluation of the EPS side effect is conducted using
Cebus monkeys.
The synthetic route to the dihydroimidazoisoquinoline core is
exemplified by the synthesis of compounds 7 and 8 (Scheme 1).
Commercially available amine 2 was converted to its formamide
Table 1
PDE inhibitory activity of amide modification analogs
MeO
MeO
N
N
S
O
N
2R3RN
Compds
NR2R3
PDE10A Kia (nM)
PDE3A Kia (nM)
PDE7A1 Kia (nM)
10
O
N
10
99
613
11
1.5
24
269
N
O
O
NH
12
13
4.3
40
828
550
507
NH
>100000
Ph
a
Values are means of two experiments.

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2585–2589
2587
MeO
MeO
favorable
p–p stacking through face-to-face interactions with
8
Phe729 and edge-to-face with Phe696. The thiazole positioned
above the long aliphatic side chain of Met713 is in direct van der
Waals contact with Met713 and Phe729 and makes a favorable
hydrophobic interaction with these two residues. In addition, the
C-2 of the thiazole projects toward the protein surface, suggesting
the amide moiety of compound 1 off the C-2 position of thiazole
should be solvent exposed. There is no direct contact of compound
7 with Mg+2 and Zn+2 present in the active site. The deep pocket in
the catalytic subunit allows SAR development in this area. Addi-
tionally, Gly725 in PDE10A is replaced with a larger amino acid
in all other PDEs. The larger side chain in other PDE enzymes
blocks access to this lipophilic pocket (selectivity pocket). There-
fore, the SAR development at the C-9 position could provide oppor-
tunities to improve the selectivity against other PDE enzymes.
Since the amide moiety is not crucial for the PDE10A inhibitory
activity, subsequent SAR development was focused on the 20-
amide modification on the thiazole (Table 2). The 20-methyl analog
(14) decreased the PED10A inhibitory activity. The introduction of
a methyl at the 40-position of 14 did not improve the potency
(Ki = 146 nM). However, replacement of the 20-methyl with a
hydroxymethyl (15), morpholinyl (16), morpholinylmethyl (17)
or homomorpholinylmethyl (18) restored the enzyme inhibitory
activity. These modifications improved PDE7A1 selectivity. Com-
pared to compound 1, compound 18 improved PDE10A inhibitory
activity and PDE3A selectivity. However, there was no plasma drug
exposure in the rat PK screen. .
N
PDE10A Ki= 35 nM, LE= 0.46
PDE3A Ki= 555 nM; PDE7A1 Ki= 3701 nM
Other PDEs Ki > 2000 nM
9
3
N
S
2'
Rat PK AUC (10 mg/kg, PO)= 0.57 µM.h
Brain concentration (6-h) < 10 ng/g (LOQ)
hERG (IonWorks): 26% inhibition @ 10 µM
Solubility (2% DMSO @ pH= 7.4 ) > 200 µM
N
7
MW= 313.4, PSA= 49
cLogP= 2.6, cLogD= 2.6
pKa= 4.3
Figure 2. In vitro and PK profile of 7.
Phe729
Gln726
Gly725
Zn
Mg
Tyr693
Met713
Phe696
Figure 3. X-ray crystal structure of 7 bound to PDE10A cyclic nucleotide binding
At this stage, it was hypothesized that the C-3 of compound 7
was another potential metabolic site. In order to block this site of
metabolism, a 3-methyl analog (compound 8) was synthesized
and evaluated. In comparison with compound 7, compound 8 is
more potent against PDE10A, has a better selectivity profile, and
improves the plasma drug exposure in the rat dramatically. While
compound 8 significantly reduced the in vitro hepatocyte clear-
ance in the human and rat compared to the lead compound 1, it
did not reduce the in vitro hepatocyte clearance in the monkey
(Fig. 4).
Concurrent SAR development was aimed at exploring alterna-
tives to the thiazole. A variety of thiazole replacements are toler-
ated at the C-1 position (Table 3). Compound 20, the 5-oxazolyl
analog, is an equipotent PDE10A inhibitor to compound 7, and
has a better selectivity profile. However, it has high hepatocyte
clearance in human and monkey (25 and 67 uL/min/106 cells).
The 4-thiazolyl (19), 4-oxazolyl (21), N-methyl-5-imidazolyl (22),
region. RCSB ID code: rcsb070261; PDB ID code: 4DFF.
MK-801-iduced hyperactivity at 30 mg/kg orally. The brain drug
level was significantly increased at an hour after oral dosing
(2.5 lg/g) compared to compound 1. The low molecular weight
of 7 allowed SAR development to improve the potency and drug
exposure in the plasma and brain to improve the in vivo activity.
The co-crystal structure of compound 7 bound within the cata-
lytic subunit of human PDE10A is shown in Figure 3. According to
this structure, there are two key interactions between compound 7
and the protein. The first interaction is the bidentate hydrogen-
bonding between the two methoxy groups of the dihydroisoquin-
oline and the conserved glutamine Gln726, in which the two meth-
oxy groups share the N–H of the glutamine residue. In the second
interaction, the phenyl of the dihydroisoquinoline occupies the
hydrophobic region defined by Phe729 and Phe696 achieving
Table 2
PDE inhibitory activity of C-20 modification analogs
MeO
MeO
N
N
S
R
4'
2'
N
Compds
NR2R3
PDE10A Kia (nM)
PDE3A Kia (nM)
PDE7A1 Kia (nM)
14
15
CH3
CH2OH
186
26
na
540
na
4596
N
N
16
17
O
O
26
177
148
2472
4599
6.6
N
18
3.8
224
3770
O
a
Values are means of two experiments.

2588
MeO
MeO
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2585–2589
The plasma unbound fraction in the rat is 16.6%. In the in vivo
study, compound 35 inhibited MK-801-induced hyperactivity at
3 mg/kg and displayed a 10-fold separation between the minimal
effective doses for inhibition of MK-801-induced hyperactivity
and hypolocomotion in rats. Evaluation of this compound for the
potential of akathisia/EPS side effects was conducted in the Cebus
monkey at 3 and 6 mg/kg dosed orally. There was no effect ob-
served at these doses. The plasma drug concentration for these
studies is not available to determine the therapeutic index based
on plasma exposure.
PDE10A Ki= 20 nM, LE= 0.46
PDE3A Ki= 968 nM, PDE7A1 Ki= 6119 nM
Other PDEs Ki > 7100 nM
N
3
N
1
S
Rat PK AUC (10 mg/kg, PO)= 7.2 µM.h
Brain concentration (6-h) < 10 ng/g (LOQ)
N
8
µ
Monkey PK AUC (3 mg/kg, PO)= 0.02 M.h
Heptocyte clearance: 7.5 µL/min/106 cells (human)
9.2 µL/min/106 cells (rat)
MW= 327.4, PSA= 49
cLogP= 3.1, cLogD= 3.1
pKa= 5.0
6
µ
65.5 L/min/10 cells (monkey)
hERG (IonWorks): 10% inhibition @ 10 µM
Solubility (2% DMSO @ pH= 7.4 ) > 150 µM
In addition to the pyridyl compound 35, the 5-pyrimidine com-
pound 37 showed promising activity and dramatically improved
the selectivity against PDE3A. This compound will be followed up
in the future.
According to the co-crystal structures of PDE10A and 7, it ap-
pears that substitutions at the 5-position should be tolerated.
Therefore, a methyl group was introduced into the 5-position of
35 to block the potential metabolic hydroxylation. While the 5-
methyl analog improved the potency (PDE10A Ki = 12 nM), the
PDE3A selectivity remained a potential issue (97% inhibition at
Figure 4. In vitro and PK profile of 8.
cyclohexyl (23) and phenyl (24) analogs reduced the PDE10A
inhibitory activity.
The introduction of a substituent into the meta-position of the
phenyl ring of 24 resulted in the restoration of the PDE10A activity
(compounds 26, 29, 31, 32, and 33). Molecular modeling studies
indicated this position superimposes well with the amide moiety
in compound 1. Unfortunately, while several potent compounds
were found, these compounds all have high hepatocyte clearance
(>14, 61, and 66 uL/min/106 cells for human, rat and monkey)
3
lM).
Encouraged by the improved in vitro and PK profile observed in
compound 8, the C-3 methyl analog of 35 was evaluated. Com-
pared with compound 35, the C-3 methyl analog 38 improved
the PDE3A selectivity and plasma drug exposure in rat, and re-
duced hepatocyte clearance in the human, rat and monkey
(Fig. 6). Future studies will entail the evaluation of 38 with
in vivo models of schizophrenia.
In summary, our SAR development has identified a series of
dihydroimidazoisoquinolines as potent, selective and orally active
PDE10A inhibitors. These analogs generally have good drug-like
properties with an overall CNS MPO desirability score (central ner-
vous system multiparameter optimization)12 >5 for many of the
compounds. The in vitro hepatocyte clearance trend in the rat for
this series of compounds appears to track with the in vivo expo-
and low or no plasma drug exposure (AUC = 0–0.15
rat PK screen.
lM h) in the
In an attempt to improve the potency of 24, the phenyl ring was
replaced with a pyridine. The 3-pyridyl compound 35 had the low-
est Ki value compared to the 2- and 4-pyridyl compounds (34 and
36). According to the crystal structures of 7 and 35, the nitrogen of
the thiazole on 7 superimposes with the nitrogen of the pyridine
on 35. Compound 35 is an equipotent PDE10A inhibitor to 7, but
less selective against PDE3A. It reduced hepatocyte clearance in
all tested species. Compared with 1, it significantly improved the
plasma drug exposure in the rat, but not in the monkey (Fig. 5).
Compound 35 is not a P-gp substrate (Caco-2 efflux ratio = 1.4).
Table 3
PDE inhibitory activity of C-1 modification analogs
MeO
MeO
N
N
1
R'
Compds
R
PDE10A Kia (nM)
PDE3A Kia (nM)
PDE7A1 Kia (nM)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
4-Thiazolyl
5-Oxazolyl
4-Oxazolyl
N-Me-5-imidazolyl
Cyclohexyl
Phenyl
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-OMe-Ph
3-OMe-Ph
4-OMe-Ph
3-Br-Ph
3-OEt-Ph
3-(4-Mopholinyl)-Ph
2-Pyridyl
3-Pyridyl
4-Pyridyl
5-Pyrimidyl
861
31
na
1738
na
na
na
na
na
954
na
na
136
na
1279
277
1472
na
449
na
14% @ 3
na
11085
na
na
na
na
Na
6935
na
na
5536
na
10114
3760
7499
na
508
264
199
121
628
33
183
212
30
114
32
8.0
6.4
240
29
na
na
101
40
lM
13% @ 3 lM
a
Values are means of two experiments.

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2585–2589
2589
MeO
MeO
ification dramatically improved PDE3A selectivity in a series of 4-
substituted-6,7-dimethoxyquinazoline PDE10A inhibitors.13
PDE10A Ki= 29 nM, LE= 0.45
PDE3A Ki= 449 nM, PDE7A1: 45% inh. @ 3 µM
Other PDEs Ki > 4274 nM
5
N
3
N
Acknowledgments
Rat PK AUC (10 mg/kg, PO)= 4.2 µM.h
Brain concentration (6-h) < 10 ng/g (LOQ)
Monkey PK AUC (3 mg/kg, PO)= 0.25 µM.h
Caco2 Efflux ratio: 1.4
N
35
The authors would like to thank Drs. John Hunter, Malcolm
MacCoss, Eric Parker and John Piwinski for their support, discus-
sion and suggestions and Ms. Terasa Andreani for preparation of
the intermediate 4.
Rat PPB= 83.4%
MW= 307.4, PSA= 49
cLogP= 2.6, cLogD= 2.6
pKa= 3.5
Heptocyte clearance: 1.7 µL/min/106 cells (human)
11.8 µL/min/106 cells (rat)
38.7 µL/min/106 cells (monkey)
hERG (ionWorks): 24% inhibition @ 10 µM
Solubility (2% DMSO @ pH= 7.4 ) > 200 µM
References and notes
1. Schmidt, C. J.; Chapin, D. S.; Cianfrogna, J.; Corman, M. L.; Hajos, M.; Harms, J. F.;
Hoffman, W. E.; Lebel, L. A.; McCarthy, S. A.; Nelson, F. R.; Proulx-LaFrance, C.;
Majchrzak, M. J.; Ramirez, A. D.; Schmidt, K.; Seymour, P. A.; Siuciak, J. A.;
Tingley, F. D., III; Williams, R. D.; Verhoest, P. R.; Menniti, F. S. Pharmacol. Exp.
Ther. 2008, 325, 681. and references cited therein.
Figure 5. In vitro and PK profile of 35.
2. Newcomer, J. W. CNS Drugs 2005, 19, 1.
3. Casey, D. E. Am. J. Med. 2005, 118, 15S.
4. Taylor, D. M. Acta Psychiatr. Scand. 2003, 107, 85.
MeO
MeO
PDE10A Ki= 25 nM, LE= 0.43
PDE3A Ki= 727 nM, PDE7A1 Ki= 5982 nM
Other PDEs Ki > 7950 nM
5. Niewoehner, U.; Bauser, M.; Ergueden, J.; Flubacher, D.; Naab, P.; Repp, T.;
Stoltefuss, J.; Burkhardt, N.; Sewing, A.; Schauer, M.; Schlemmer, K.; Weber, O.;
Boyer, S. J.; Miglarese, M. PCT Int. Appl. WO 2002048144, 2002.
6. Maier, T.; Graedler, U.; Baer, T.; Vennemann, M. PCT Int. Appl. WO 2005002579,
2005.
7. Sugiyama, A.; Satoh, Y.; Hashimoto, K. J. Cardiovasc. Pharmacol. 2001, 38, 268.
8. Van de Water, A.; D’Aubioul, J.; Van Gerven, W.; De Chaffoyde Courcelles, D.;
Freyne, E.; Xhonneux, R.; Reneman, R. S.; Janssen, P. A. J. Arch. Int. Pharmacodyn.
Ther. 1992, 60.
9. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.; Broske,
L.; Prelusky, D.; Nomeir, A.; White, R. E. Rapid Commun Mass Spectrom. 2001, 15,
335. The animal was dosed 10 mg/kg orally. The plasma drug exposure was
measured from 0 to 6 h, and the brain drug concentration was measured after
6 h. The brain/plasma ratio is the ratio of brain and plasma drug concentration
at 6-h.
N
9
N
Rat PK AUC (10 mg/kg, PO)= 6.8 µM.h
Brain concentration (6-h) < 10 ng/g (LOQ)
Heptocyte clearance: 0.4 µL/min/106 cells (human)
3.6 µL/min/106 cells (rat)
5'
N
38
26.6 µL/min/106 cells (monkey)
MW= 321.4, PSA= 49
cLogP= 2.9, cLogD= 2.9
pKa= 4.0
hERG (IonWorks): 29% Inhibition @ 10 µM
Solubility (2% DMSO @ pH= 7.4 ) > 200 µM
Figure 6. In vitro and PK profile of 38.
10. Male CD rats were habituated to the locomotor activity (LMA) chambers 24 h
before testing. On test day, they were co-administered MK-801 (0.3 mg/kg, sc)
and the PDE10 inhibitor (30 mg/kg, po) and placed in the testing apparatus.
Inhibition of MK-801 induced activity was measured as a percent of activity in
the PDE10 inhibitor +MK-801group relative to the vehicle +MK-801 group.
11. Hodgson, R. A.; Hyde, L. A.; Guthrie, D. H.; Cohen-Williams, M. E.; Leach, P. T.;
Kazdoba, T. M.; Bleickardt, C. J.; Lu, S. X.; Parker, E. M.; Varty, G. B. Pharmacol.,
Biochem. Behav. 2011, 98, 181.
12. Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. ACS Chem. Neurosci. 2010, 1,
435. The softwares used to calculate physicochemical properties to obtain the
CNS MPO scores are Biobyte (cLogP), ACD/Laboratories (pKa), Pipeline Pilot
(PSA) and a hybrid model using Biobyte’s clogP and ACD/Laboratories’ pKa
developed at Schering-Plough (cLogD).
sure. Compound 35 is a potent PDE10A inhibitor with good to
excellent selectivity over other PDE enzymes except for PDE3A. It
is efficacious in the in vivo test believed to model the positive
symptoms of schizophrenia with a modest separation between
the efficacy and hypolocomotion based on the minimum effective
dose. Introduction of a methyl group at the C-3 of 35 (compound
38) improved the plasma drug exposure in the rat and significantly
reduced hepatocyte clearance in the rat and human. Future SAR
development will be focused on modifications at the C-9 position
to improve the selectivity against PDE3A by approaching the selec-
tivity pocket in the PDE10A protein. This approach has been proved
to be effective as evidenced by a recent publication that this mod-
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