Use of structure based design to increase selectivity of pyridyl-cinnoline phosphodiesterase 10A (PDE10A) inhibitors against phosphodiesterase 3 (PDE3)

Article abstract of DOI:10.1016/j.bmcl.2012.09.010

We report our successful effort to increase the PDE3 selectivity of PDE10A inhibitor pyridyl cinnoline 1 using a combination of computational modeling and structural-activity relationship investigations. An analysis of the PDE3 catalytic domain compared to the co-crystal structure of cinnoline analog 1 in PDE10A revealed two areas of structural differences in the active sites and suggested areas on the scaffold that could be modified to exploit those unique structural features. Once SAR established the cinnoline as the optimal scaffold, modifications on the methoxy groups of the cinnoline and the methyl group on the pyridine led to the discovery of compounds 33 and 36. Both compounds achieved significant improvement in selectivity against PDE3 while maintaining their PDE10A inhibitory activity and in vivo metabolic stability comparable to 1.

Full text of DOI:10.1016/j.bmcl.2012.09.010

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6938–6942
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Use of structure based design to increase selectivity of pyridyl-cinnoline
phosphodiesterase 10A (PDE10A) inhibitors against phosphodiesterase 3 (PDE3)
Essa Hu a, , Roxanne K. Kunz a, Shannon Rumfelt a, Kristin L. Andrews c, Chun Li d,
,
⇑
Stephen A. Hitchcock a,à, Michelle Lindstrom b, James Treanor b
a Department of Small Molecule Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
b Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
c Department of Molecular Structure and Characterizations, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
d Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2012
Revised 1 September 2012
Accepted 4 September 2012
Available online 21 September 2012
We report our successful effort to increase the PDE3 selectivity of PDE10A inhibitor pyridyl cinnoline 1
using a combination of computational modeling and structural–activity relationship investigations. An
analysis of the PDE3 catalytic domain compared to the co-crystal structure of cinnoline analog 1 in
PDE10A revealed two areas of structural differences in the active sites and suggested areas on the scaffold
that could be modified to exploit those unique structural features. Once SAR established the cinnoline as
the optimal scaffold, modifications on the methoxy groups of the cinnoline and the methyl group on the
pyridine led to the discovery of compounds 33 and 36. Both compounds achieved significant improve-
ment in selectivity against PDE3 while maintaining their PDE10A inhibitory activity and in vivo metabolic
stability comparable to 1.
Keywords:
PDE10A
PDE3
Phosphodiesterase
Selectivity
Cinnolines
Ó 2012 Elsevier Ltd. All rights reserved.
The use of a phosphodiesterase 10A (PDE10A) inhibitor to treat
neurological diseases such as schizophrenia has recently gathered
much attention in the research community.1,2 Currently, a majority
of the atypical antipsychotics prescribed for the treatment of
schizophrenia target the dopaminergic receptors. This shared
modality has resulted in an overlap of side effect profiles, minimal
efficacy towards the negative and cognitive symptoms, and a sub-
set of the patient population unresponsive to existing treatments.3
Recent studies indicated that inhibition of PDE10A could modulate
not only the dopaminergic pathways but also the glutamatergic
pathways. By affecting two pathways, both of which have been
implicated in schizophrenia, this novel mechanism of action could
address the current unmet medical needs: a more tolerable side ef-
fect profile, an increased efficacy towards the negative and cogni-
tive symptoms, or a treatment for the unresponsive patients.
PDE10A is one of eleven members of the phosphodiesterase
family. Reported to be highly expressed in the striatum,4 the
PDE10A enzyme hydrolyzes secondary messengers cAMP and
cGMP to AMP and GMP, respectively. The tissue specificity of
PDE10A expression makes it an ideal target for modulation of
intracellular signaling in the striatum, a region of the brain most
linked to the pathophysiology of schizophrenia. Inhibition of
PDE10A enzyme would increase the intracellular levels of cAMP
and cGMP, compensating for the aberrant signaling attributed to
the disease.5
We recently reported the discovery of cinnoline 1 as a potent
inhibitor of PDE10A (IC50 = 4.9 nM) with good in vivo rat PK
(Fig. 1).6 This compound exhibited PDE3 activity of 1.7
lM or
346 fold selectivity, which was sufficient to advance to proof of
concept studies described in our earlier report. However, with
PDE3 expression reported in heart tissue,7 we decided to increase
the selectivity window for our PDE10A inhibitors as therapeutic
candidates in order to minimize possible off-target effects. At the
same time, we needed these improvements in selectivity against
PDE3 to not compromise the in vivo metabolic stability of 1. Since
our previously disclosed SAR showed that the piperidine propanol
portion of the molecule was critical to afford low in vivo clearance
in rats, we decided to keep this moiety constant and focused our
efforts on optimization of the rest of the molecule.
Comparison of the PDE3 catalytic domain overlaid with cinno-
line 1 co-crystallized6 in the human PDE10A catalytic domain
revealed two key binding regions where the amino acid residues
differed (Fig. 2). The first key region was found in the channel
region depicted in green.8 The channel-like pocket was formed in
the PDE10A enzyme as a result of Gly715 adjacent to the conserved
Gln716 and Met703 (Fig. 2A). In contrast, the same region of the
⇑
Corresponding author. Tel.: +1 805 313 5300.
E-mail address: ehu@amgen.com (E. Hu).
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins
Drive, San Diego, CA 92121, USA.
à
Envoy Therapeutics, 555 Heritage Drive, Jupiter, Florida 33458, USA.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.010

E. Hu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6938–6942
6939
Figure 1. Potent PDE10A inhibitor cinnoline 1.
Figure 2. Structural comparison of PDE10A and PDE3 catalytic domains. Crystal structure of 1 (green) bound in hPDE10A (4DDL.pdb, wheat) superposed with hPDE3B
(1SO2.pdb, cyan). Key residues and differences between PDE10A and PDE3B are highlighted (PDE10A/PDE3B). Surfaces corresponding to the ‘channel’ and ‘shelf are colored in
green and pink respectively’.
binding pocket in PDE3 was filled by Leu987 and Phe976 (Fig. 2B).
The overlay also appeared to suggest that the 6-methoxy group on
the cinnoline scaffold was perfectly positioned to exploit these res-
idue differences. An appropriate replacement of the methoxy
group that could fit in the channel region might increase the selec-
tivity against PDE3.
The second key region is the shelf-like contour shown in pink in
Figure 2. In PDE10A, the shelf is composed of residues Ile 701,
Pro702, Met 703, Met704, and Ser561. As shown in Figure 2A,
Scheme 1. Reagents and conditions: (a) AcCl, AlCl3; (b)HNO3, H2SO4; (c) Fe, AcOH;
(d) NaNO2, HCl, water; (e) POBr3, MeCN.
the pyridine ring on 1 made important hydrophobic contact with
Ile 701 and Met 703. While the pyridine methyl group was ob-
served to bind in two different orientations in the PDE10A homodi-
mer, the conformation shown in Figure 2 suggested that the
methyl group on the pyridine could be oriented towards a small
pocket adjacent to Ser561. With Phe976 and Ser974 replacing
Met 703 and Ile 701 in PDE3 (Fig. 2B), the pyridine ring could
not achieve significant hydrophobic contact with the protein. The
small pocket next to methyl group was also absent in PDE3 due
to the larger Thr829 residue in place of Ser561. To exploit these dif-
ferences, we hypothesized that replacement of the methyl group
on pyridine ring with functional groups that could better fill the
small pocket by Ser 561 would further discourage binding in
PDE3 and improve its selectivity.
All the scaffolds explored in this paper were either purchased
from commercial sources or synthesized using the general scheme
outlined in Scheme 1. The length of the individual syntheses could
be shorter depending on the availability of the starting material for
the desired scaffold. The order of the first two steps could also be
switched depending on the reactivity of the R1 and R2 subsituent
toward Friedel–Crafts and nitration reactions. In general, the
synthesis would start with installation of the methyl ketone onto
a suitably di-substituted compound 2 with a Friedel–Crafts reac-
tion. Nitration of methyl ketone 3 followed by iron reduction of
compound 4 produced the anilino ketone 5. Cyclization with so-
dium nitrate formed the cinnoline alcohol 6. Bromination with
phosphorous oxy-bromide afforded cinnoline bromide 7 ready
for Suzuki coupling.
On a few occasions, additional functionalization of the cyclized
6,6-fused ring scaffold was performed prior to Suzuki coupling
(Scheme 2). In example 2A, the commercially available 6,7-dimeth-
oxyisoquinolin-1(2H)-one (8) was alkylated to form N-ethyl iso-
quinolinone 9 followed by treatment with bromine in acetic acid
to produce the isoquinolinone bromide 10 ready for Suzuki cou-
pling. In example 2B, cyclized 4-bromo-7-fluoro-6-methoxycinno-
line (11) was further functionalized by treatment with LHMDS and
cyclopropylmethanol to form 4-bromo-7-(cyclopropylmethoxy)-
6-methoxycinnoline (12) before Suzuki coupling.

6940
E. Hu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6938–6942
Table 1
Effect of electronics and ring size on PDE10A potency
Compound#
R =
PDE10 IC50 (nM)
7.6
21
Scheme 2. Reagents and conditions: (a) NaH, EtBr, DMF, 95% yield; (b) Br, AcOH,
68% yield; (c) LHMDS, DMF; 83% yield.
22
23
47
1090
Before implementing structural changes suggested by modeling
to improve selectivity against PDE3, we first wanted to ascertain
that the cinnoline scaffold was the optimal template for binding
to PDE10A. As illustrated in Table 1, cinnoline 21 exhibited PDE10A
inhibitory activity in the single digit nM range (IC50 = 7.6 nM).
Replacement of the cinnoline with an isoquinoline (22) led to a
six fold loss in potency. This seemed to suggest the cinnoline nitro-
gens have an important interaction in the PDE10A binding pocket.
Indeed, the crystal structure of 1 showed that the cinnoline nitro-
gens form water mediated hydrogen bond s with the protein. A
more dramatic loss in potency was observed when the 6,6-fused
ring system was replaced with a 6,5-fused ring. Benzoisothiazole
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2CO3; (b) isopropylamine,
DMSO, 90 °C.
23 was measured to possess 1 lM potency against PDE10A. This
difference in 6,6-fused versus 6,5-fused ring sizes for the scaffold
Syntheses of both cinnolines used in scaffold SAR studies began
with Suzuki coupling of their respective fluoro-pyridine boronic
acids as shown in Scheme 3. Intermediate 14 was formed by SNAr
displacement of fluoro-pyridine 13 with isopropyl amine. As
shown in Scheme 4, the piperidine propanol used to make cinno-
line 16 was prepared from commercially available piperidine ethyl
ester (17). N-alkylation using sodium hydride and benzyl bromide
afforded the benzyl piperidine ester 18. Nucleophilic addition with
methyl lithium formed the tertiary alcohol 19. Hydrogenation re-
moved the benzyl protecting group. Lastly, SNAr displacement of
fluoro-methyl-pyridine 15 with piperidine propanol 20 afforded
compound 16.9
Table 2
SAR of 6,6-Fused System
Compound# R1
=
PDE10 IC50
(nM)
RLM (lL/
(min⁄mg))
1
4.9
11.9
13.4
60
24
25
57
69
26
13.8
50
Scheme 4. Reagents and conditions: (a) NaH, BnBr, DMF, 95% yield; (b) MeLi, THF;
(c) Pd/C, H2, 75% two step yield; (c) DMSO; 55–87% yield.

E. Hu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6938–6942
6941
Table 3
Examination of the substitution on the cinnoline
Compound#
R2
=
R3
=
PDE10 IC50 (nM)
PDE3 IC50 (nM)
Selectivity (fold)
1
OCH3
OCH3
OCH3
OCH3
OCH2CH3
CH3
N(CH3)2
O(cPr)
OCH3
F
OCHF2
OCH2(cPr)
CH3
OCH3
OCH3
OCH3
4.9
1700
347Â
>75Â
231Â
>523Â
>244Â
980Â
—
27
28
29
30
31
32
33
132
68.6
19.1
40.9
25.6
4500
4.1
>10,000
15,900
>10,000
>10,000
25,100
>10,000
17,900
4365Â
would change the angle of trajectory of the pyridine side chain in
the shelf-like region in PDE10A. The 143 fold difference in PDE10A
affinity between 21 and 23 clearly indicated that the trajectory of
6,6-fused system is preferred to 6,5-fused system.
group at the 7-position and an ethoxy group at the 6-position of
the cinnoline was eightfold less potent than cinnoline 1. All the
modifications at the 7-position examined afforded at best little
improvement in selectivity but all were detrimental to the PDE10A
activity.
We next examined the effect of small electronic changes on the
6,6-fused ring system on PDE10A potency (Table 2). Compared to
1, removal of either one of the two nitrogens on the cinnoline scaf-
fold produced a comparable effect on potency and metabolic sta-
bility. Quinoline 24 exhibited a PDE10A inhibitory activity of
11.9 nM, about 2 fold less potent than cinnoline 1. Isoquinoline
25 afforded a PDE10A IC50 of 13.4 nM, nearly threefold less potent
than 1. Neither modifications, however, appeared to have a signif-
icant impact on their in vitro rat liver microsomal clearances. Inter-
estingly, N-ethyl-isoquinolinone 26, with the additional steric bulk
of the amide carbonyl and the ethyl substituent, was found to ex-
hibit potency (PDE10A IC50 = 13.8 nM) and metabolic stability
We next turned to modification of the substituent at the 6-
position of the cinnoline (Table 3). Keeping the 7-methoxy group
constant, replacement of the methoxy group at the 6-position with
a methyl group (31) resulted in a decrease of PDE10A inhibitory
activity (PDE10A IC50 = 25.6 nM). Use of dimethylamine substitu-
ent (32) led to significant reduction in potency as it most likely dis-
rupted the critical hydrogen bonding interaction with the
conserved Gln716. Gratifyingly, installation of a cyclopropyl sub-
stituent (33) at the 6-position not only maintained the single digit
nM potency (PDE10A IC50 = 4.1 nM) but also increased selectivity
against PDE3 to greater than 4000 fold. Presumably, the cyclopro-
pyl group was an appropriate size to extend into the channel-like
pocket in PDE10A and thus reduce its affinity for PDE3.
To explore the residue differences in the shelf-like region high-
lighted in Figure 2, we examined the SAR of the methyl substituent
on the pyridine ring on cinnoline 1. Based on the co-crystal structure
in PDE10A, the pocket in the vicinity of cinnoline methyl pyridine
appeared small. Thus, only small modifications on the methyl group
were examined. As shown in Table 4, replacement of the methyl
group with a chlorine atom (34) produced minimal impact on both
PDE10A potency and PDE3 selectivity. Bulkier cyclopropyl group
(35) further increased PDE10A inhibitory activity to 1.3 nM and in-
creased the PDE3 selectivity to greater than 2000 fold. Lastly, difluo-
romethyl analog 36 not only preserved the increase in PDE10A
activity (PDE10A IC50 = 1.2 nM) but further widened the window
of selectivity against PDE3 to greater than 5000 fold. It is worth not-
ing that 35 and 36, the two analogs with the greatest improvement
in PDE10A potency and PDE3 selectivity also possessed both the
highest and the lowest of calculated logP values amongst the com-
pounds examined in Table 4. Thus the SAR trends was not likely to
be due to the modest logP differences amongst the analogs.
Both analogs 33 and 36 with improved selectivity against PDE3
were then profiled for their metabolic stability (Table 5). In vivo
rat PK studies (dosed at 1 mg/kg IV in DMSO and 5 mg/kg PO in
Tween/HPMC/water) showed both compounds achieved compara-
ble clearance, T1/2 and acceptable oral bioavailability compared to 1.
In conclusion, starting with compound 1 which was optimized
for in vivo metabolic stability, we were able to use computational
(RLM = 50
l
L/(min⁄mg)) comparable to its less bulky isoquinoline
analog (25). Overall, the cinnoline scaffold exhibited superior
PDE10A potency compared to the other scaffolds investigated in
Table 1 and Table 2. This finding assured us that the cinnoline scaf-
fold was optimal and that we could proceed with implementation
of modifications designed to exploit the structural differences be-
tween PDE10A and PDE3 binding regions.
We had previously disclosed that the two methoxy groups on
the cinnoline formed a bidentate hydrogen bond with the con-
served glutamine (Gln716) based on an X-ray co-crystal structure
of a cinnoline analog in PDE10A enzyme.6 Structural overlap of
PDE10A co-crystal structure with PDE3 catalytic domain seemed
to suggest that one of the methoxy groups was also perfectly posi-
tioned to access the channel-like pocket that exists in PDE10A but
not in PDE3. To test this hypothesis, both methoxy groups were
modified and their respective analogs were tested for PDE10A
potency and PDE3 selectivity. We first examined substitution effect
on the 7-methoxy position of the cinnoline, the position that
should not impact selectivity against PDE3 based on the structural
overlap (Table 3). Compared to cinnoline 1, replacement of the
7-methoxy group with a small but electronegative fluoride atom
(27) resulted in nearly 26 fold loss in PDE10A potency. Restoring
the alkoxy linkage with a difluoromethoxy group (28) did not
afford single digit nM activity. Installation of a cyclopropylmeth-
oxy group (29) did improve the selectivity against PDE3 compared
to 1, however, its inhibitory activity against PDE10A remained
modest (IC50 = 19.1 nM). Meanwhile, compound 30 with a methyl

6942
E. Hu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6938–6942
Table 4
SAR of R4 position on the pyridine ring
Compound#
R4
=
clogP
PDE10 IC50 (nM)
PDE3 IC50 (nM)
Selectivity (fold)
1
CH3
Cl
cPr
3.10
3.31
3.54
2.79
4.9
6.3
1.3
1.2
1700
2250
2980
6630
347Â
34
35
36
357Â
2292Â
5525Â
CHF2
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Table 5
Comparison of in vitro and in vivo Rat PK profiles
Compound#
Cl (L/hr/kg)
T1/2 (hr)
%F (%)
1
33
36
1.29
0.93
0.80
1.54
1.48
2.08
60
32
46
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6. (a) Hu, E.; Kunz, R. K.; Rumfelt, S.; Chen, N.; Burli, R.; Li, C.; Andrews, K. L.; Zhang,
J.; Chmait, S.; Kogan, J.; Lindstrom, M.; Hitchcock, S. A.; Treanor, J. Bioorg. Med.
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cinnoline 1 in human PDE10A in our paper cited in Ref. 6a. PDB ID number for the
coordinates of the co-crystal structure is 4DDL.
modeling and X-ray co-crystal structure analyses to discern key re-
gions of the molecule that could be modified to enhance the win-
dow of selectivity against PDE3. The cinnoline scaffold was first
confirmed to be the optimal scaffold after examining a series of
close analogs. Compound 33 was identified as the analog that best
exploited the channel-like difference in the catalytic domains be-
tween PDE10A and PDE3, which afforded greater than 4000 fold
selectivity against PDE3 while maintaining its PDE10A inhibitory
activity of 4.1 nM. Compound 36 was able to increase its interac-
tion with the unique structur of the PDE10A shelf-like region com-
pared to 1, resulting in an improvement in selectivity against PDE3
to greater than 5000 fold and an increased inhibitory activity
against PDE10A (IC50 = 1.2 nM). Our strategy to keep constant the
piperidine propanol region, critical to the in vivo metabolic stabil-
ity of 1 led to both 33 and 36 exhibiting favorable in vivo rat PK
profile comparable to 1. With a combination of computation mod-
eling analyses and SAR investigation, we have discovered two can-
didates both with single digit PDE10A potency, greater than 4000
fold PDE3 selectivity, and suitable metabolic stability for further
in vivo studies.
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Sci. 1990, 79, 236; (b) Varnerin, J. P.; Chung, C. C.; Patel, S. B.; Scapin, G.; Parmee,
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Hockman, S.; Kambayashi, J.; Manganiello, V. C.; Liu, Y. Cell. Signal. 2007, 19,
1765.
8. A similar strategy that lead to 100Â PDE3 selectivity of PDE10A inhibitor was
recently reported: Helal, C. J.; Kang, Z.; Hou, X.; Pandit, J.; Chappie, T. A.;
Humphrey, J. M.; Marr, E. S.; Fennell, K. F.; Chenard, L. K.; Fox, C.; Schmidt, C. J.;
Williams, R. D.; Chapin, D. S.; Siuciak, J.; Lebel, L.; Menniti, F.; Cianfrogna, J.;
Ronseca, K. R.; Nelson, F. R.; O’Connor, R.; MacDougall, M.; McDowell, L.; Liras, S.
J. Med. Chem. 2011, 54, 4536.
9. (a) For more details on synthetic preparations and PDE10A assay conditions,
CAR model, see: Hu, E.; Kunz, R.; Nixey, T.; Hitchock, S. Preparation of quinoline
derivatives and their aza analogs as phosphodiesterase 10 inhibitors.
WO2009025839.; (b) Hu, E.; Kunz, R.; Chen, N.; Nixey, T.; Hitchcock, S.
Preparation of quinoline derivatives and their aza analogs as
phosphodiesterase 10 inhibitors. WO2009025823.; (c) Arrington, M. P.; Liu, R.;
Hopper, A. T.; Conticello, R. D.; Nguyen, T. M.; Gauss, C. M.; Burli, R.; Hitchcock,
S. A.; Hu, E.; Kunz, R. Cinnoline derivatives as phosphodiesterase 10 inhibitors,
their preparation, pharmaceutical compositions, and use in therapy.
WO2007098169.
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