Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.07.054

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Full text of DOI:10.1016/j.bmcl.2016.07.054

Accepted Manuscript
Discovery of Novel Potent Imidazo[1,2-b]pyridazine PDE10a Inhibitors
Sanath K. Meegalla, Hui Huang, Carl R. Illig, Daniel J. Parks, Jinsheng Chen,
Yu-Kai Lee, Kenneth J. Wilson, Sharmila K. Patel, Wing S. Cheung, Tianbao
Lu, Thomas Kirchner, Hossein B. Askari, John Geisler, Raymond J. Patch, Alan
C. Gibbs, Brian Rady, Margery Connelly, Mark R. Player
PII:
S0960-894X(16)30782-X
http://dx.doi.org/10.1016/j.bmcl.2016.07.054
BMCL 24098
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 June 2016
21 July 2016
22 July 2016
Please cite this article as: Meegalla, S.K., Huang, H., Illig, C.R., Parks, D.J., Chen, J., Lee, Y-K., Wilson, K.J., Patel,
S.K., Cheung, W.S., Lu, T., Kirchner, T., Askari, H.B., Geisler, J., Patch, R.J., Gibbs, A.C., Rady, B., Connelly,
M., Player, M.R., Discovery of Novel Potent Imidazo[1,2-b]pyridazine PDE10a Inhibitors, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.07.054
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Bioorganic & Medicinal Chemistry Letters
Discovery of Novel Potent Imidazo[1,2-b]pyridazinePDE10a Inhibitors
Sanath K. Meegalla, Hui Huang, Carl R. Illig, Daniel J. Parks, Jinsheng Chen, Yu-Kai Lee, Kenneth J.
Wilson, Sharmila K. Patel, Wing S. Cheung, Tianbao Lu, Thomas Kirchner, Hossein B. Askari, John
Geisler, Raymond J. Patch, Alan C. Gibbs, Brian Rady, Margery Connelly and Mark R. Player*
Janssen Research & Development, Welsh and McKean Roads, Spring House, PA 19477-0776, USA
ARTICLE INFO
ABSTRACT
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are
described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an
insulin secretagogue in vitro and in vivo.
Article history:
Received
Revised
Accepted
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
PDE10a inhibitor, insulin secretagogues,
type 2 diabetes, GPCR, GSIS, brain penetration
phenotype of the PDE10a knockout mice which were resistant to
weight gain on a high fat diet, without an appreciable change in
food consumption.5 The differences in weight between the
PDE10a knockout and wild type mice were predominantly due to
differences in adiposity, and not lean mass. When compared to
wild type mice, the PDE10a knockout mice had lower plasma
insulin, triglycerides, non-esterified free fatty acids and leptin.3
These data suggest that PDE10a inhibitors may be
beneficial for the treatment of Type 2 diabetes and obesity, while
potentiating GSIS with the potential for weight loss. Since
compounds that cross the blood brain barrier may exhibit
potential CNS side effects due to the high expression levels of
PDE10a in the brain, identifying peripherally restricted PDE10a
inhibitors with excellent sub-type selectivity and the desired
efficacy was the major focus of project. Herein is reported an
account of the our efforts on the investigation of peripherally
restricted PDE10A inhibitors.
Phosphodiesterases (PDEs) are a family of enzymes
encoded by 21 genes subdivided into 11 distinct families
according to structural and functional properties. These enzymes
are hydrolases that metabolically inactivate widely occurring
intracellular second messengers, 3′,5′-cyclic adenosine
monophosphate
(cAMP)
and
3′,5′-cyclic
guanosine
monophosphate (cGMP), by catalytic hydrolysis of the 3′-ester
bond, while forming the inactive 5′-monophosphate. On the basis
of substrate specificity, the PDE families can be divided into
three groups: i) the cAMP-specific PDEs, which include PDE4, 7
and 8; ii) the cGMP-specific enzymes PDE5, 6 and 9; and iii) the
dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10 and 11.1
Although PDE10a is predominantly expressed in the brain, it is
also expressed in neuroendocrine tissues such as pancreatic islets,
adrenal gland, pituitary gland, and in neuronal ganglia throughout
the intestine.1, 2
In pancreatic islet β-cells, incretins activate the GLP-1
receptor, an adenylate cyclase (AC)-coupled GPCR (G-protein
coupled receptor), which elevates intracellular cyclic adenosine
mono-phosphate (cAMP) levels. Because cAMP is a major
regulator of glucose-stimulated insulin secretion (GSIS) from
pancreatic islet β-cells, inhibition of the PDE10a activity may
results in the enhancement of cAMP levels with concomitant
insulin secretion.3
An internally identified imidazo[1,2-b]pyridazine
PDE10a chemotype4 (Fig. 1), first investigated for CNS
disorders, was chosen as the lead structure in our investigation.
The imidazo[1,2-b]pyridazine 1 occupies the hydrophobic clamp
of the PDE10a catalytic site that recognizes the adenosine or
guanosine ring structures of cAMP or cGMP while interacting
with the conserved Gln-716. The N-linked morpholine acts as a
hydrogen bond acceptor from the tightly-bound buried water
molecules that are an integral part of the structure of the enzyme.
The alkyl ether side chain-attached pyridine can exert
hydrophobic interactions with protein outside the catalytic site.1
The presence of the C-3 aryl substituent increases the potency of
the compounds. The substituent on the aryl group on the other
A peripherally-restricted PDE10a inhibitor has been
shown to enhance insulin secretion and reduce glucose excursion
in lean Wistar rats.2 Further validation that PDE10a inhibition
may have beneficial effects on controlling obesity comprises the
_________________________
* To whom correspondence should be addressed.
Phone: 215-628-7860. E-mail: mplayer@its.jnj.com

hand is solvent exposed and does not exhibit any appreciable
contribution to potency of the substrate.
A. Quinoline linked via an oxymethyl tether
H20
Gln-716
Selectivity
Pocket
Metal binding
site
1
Figure 1. Imidazo[1,2-b]pyridazine binding interactions
B. Quinoline linked via an alkene tether
The structure-based drug design efforts identified a
unique “selectivity pocket” adjacent to the catalytic site of
PDE10a enzyme and interactions within this pocket allowed the
design of highly selective and potent PDE10A inhibitors. In this
context, the “2-methylenoxy quinoline” was identified as one
of the optimum substituents in the investigated PDE10a
inhibitors (Fig. 2).6
2
PDE10A IC50: 0.3 nM
> 1000 fold selective vs. other PDEs
Figure 2. PDE10A inhibitor with 2-methylenoxy quinoline selectivity
pocket substituent
C. Quinoline linked via an alkane tether
EPS-like side effects have been observed in pre-clinical
species when dosed with centrally active PDE10a inhibitors.
Although these may be considered minor and/or tolerable side
effects for an anti-psychotic agent if observed in humans, they
would not be acceptable for an anti-diabetic therapy. Thus, as a
starting point it was decided to attach a “selectivity pocket”
substituent to the imidazo[1,2-b]pyridazine core structure bearing
a hydrophobic aryl substituent containing a polar substituent at
the C-3 position (Fig. 3). This design was contemplated as a way
of restricting the brain penetration of the compounds by
increasing the polar surface area of the molecule with minimal
interference with core binding interactions. The quinoline
selectivity pocket substituent could potentially interact with Tyr
683 to improve the potency and the subtype selectivity. The
close geometric shape, the ease of the synthesis and minimal
perturbation of the electronic nature of the central core led us to
choose the 2-oxymethyl quinoline instead of the 2-methylenoxy
quinoline as a potential selectivity pocket substituent at the 2-
position of the core structure based on molecular modeling
studies (Fig. 4).
D. Quinoline linked via an 1,4-trans cyclobutane tether
Figure 3. A 2-oxymethylene quinoline-appended imidazopyridazine
Figure 4. Models of quinoline attached via various linkers to imidazo[1,2-
b]pyidazine bound to PDE10a
Although it also may have been possible to introduce a
substituent at the C-6 position that could interact with a Zn+2 ion
at the metal binding site to enhance the potency, potential
undesirable selectivity issues precluded this strategy.
Structure-based drug design entailed docking virtual
compounds of potential interest into a crystal structure of
PDE10a (PDB ID: 5K9R) using Glide.7 Flexible ligand docking
revealed a common low-energy binding mode (Figure 4) which
correlates well with observed SARs for the imidazopyridazine
series.
The compounds bind PDE10a with the
imidazopyridazine: N-1 interacting with Q716; and the aromatic

core -stacked between F719 and F686 (the aforementioned
hydrophobic clamp). The 2-oxymethyl quinolones reside in the
selectivity pocket (“8 o’clock” region of Figure 4) in contrast to
the morpholines which are buried and interact with “structural”
water molecules.
The synthetic routes for the preparation of two carbon atom
bridged 2-quinolyl imidazolopyridazines are shown in the
Scheme 2. Oxidation of the primary alcohol 9 with active MnO2
or Dess-Martin reagent yielded the aldehyde 10 which served as
a key intermediate for the preparations of all three linkers. The
installation of the aryl substituent was accomplished by the Pd-
catalyzed Heck type coupling of the desired aryl bromide with
aldehyde 10 to produce 11 in good yields. A TMSCl-catalyzed
Knoevenagel-type condensation9 of the aldehyde 11 and 2-
methylquinoline produced the desired imidazopyridazine 12. The
transition metal-catalyzed selective reduction of the alkene
moiety to obtain the corresponding saturated linker was
complicated by the competitive reduction of the core ring system.
Nevertheless, this transformation was successfully carried out
using tosyl hydrazide as the reducing agent10 to yield the target
13. The aldehyde 11 was employed in Seyferth-Gilbert
homologation using dimethyl diazo-2-oxopropylphosphonate to
afford the terminal alkyne 14 which was then employed in a
Sonogashira coupling with 2-bromoquinoline to furnish the
alkyne linked quinolone compound 15.
The pyridazine ring structure was assembled via a
cyclocondensation reaction of Cl, Br-pyridazine amine 3 with
ethyl bromopyruvate. The displacement of the bromine of
4
with morpholine afforded 5 which was then de-chlorinated with
Pd/C, HCOONH4 to obtain 6 which served as a key intermediate
for the preparation of most of the desired analogues. Reduction
of the ester followed by NBS bromination produced 7 which was
then subjected to Suzuki coupling to introduce the C-3 aryl
substituent. The K-salt of the Suzuki product was reacted with 2-
Cl-quinoline in the presence of 18-crown-6 to furnish the final
product 8.
Scheme 1. Preparation of imidazo[1,2-b]pyridazines attached to quinolone
via an oxymethylene linker
Scheme 2: Preparation of imidazo[1,2-b]pyridazines attached to quinolone
via alkene and alkyne linkers
Reagents and conditions: (a) ethyl bromopyruvate, DMF, rt; (b) morpholine,
DIEA, CH3CN, rt, 3 h; (c) 10% Pd/C, HCOONH4, THF, reflux; (d) (i). LAH,
THF, 0 °C rt, 3 h (ii) NBS, CH3CN, -20 °C rt, 2 h; (e) (i) Ar-B(OH)2,
PdCl2 dppf, 2 M Na2CO3, DME, 95 ºC, 12 h (ii) K tert-butoxide, 2-Cl-
quinoline,18-crown-6, THF, 60 ºC.
Reagents and conditions: (a) MnO2, DMF, rt, 18 h; (b) ArBr, Pd(OAc)2, Ph3P,
KOAc, DMAc, 110 °C, 22 h; (c) 2-Me-quinoline, TMSCl, DMF, 90 °C; (d)
4-methylbenzenesulfonylhydrazide, NaOAc, DME/water (10:1 (v/v)), 85 °C,
18 h; (e) dimethyl(1-diazo-2-oxopropyl)phosphonate, MeOH, rt, 48 h; (f) 2-
bromoquinoline, DIEA, CuI, Cl2(Ph3P)2Pd, DMF, rt, 2 h.
Even
though
these
2-oxymethyl
quinolyl
imidazolopyridazines are readily accessible, the compounds
possessed poor chemical stability, especially under acidic
conditions. The HCl salts of these compounds slowly underwent
decomposition to yield quinolone and the corresponding
chloromethyl imidazopyridazine fragment (Fig. 5). Usually the
acid catalyzed conversion of 2-alkoxyquinoline to 2-
hydroxyquinoline requires elevated temperatures.8 The relatively
facile hydrolysis of 2-oxymethyl quinolyl imidazolopyridazines
may be in part due to the enhanced electron deficiency of the
methylene attached to the heterocyclic core structure. While the
stability of the acid salts was improved by preparing salts with
less nucleophilic anions, e.g. mesylate, the stability of the salts
was still questionable. Replacement of the O with other
heteroatoms such as S (cpds. 26 and 30) produced analogues
which were as potent as the oxymethyl linked compounds and
exhibited better chemical stability. However the compounds
exhibited poor metabolic stability.
The affinity of the compounds for PDEs was measured by a
scintillation proximity assay using the enzyme isolated from Sf9
cells stably expressing full length human recombinant PDE10a.
The brain/plasma ratios shown in table 1 were used to evaluate
the abilities of the analogues to penetrate the brain.
As shown in Table 1, alkene- (27) and alkane- (28) linked
quinolone-containing substrates showed good in vitro PDE10a
inhibitory activities. Compound 29 with quinoline attached via an
alkyne linker, however, was 6-7 fold more potent than alkane- or
alkene-linked compounds (3 nM vs. 21 nM). Generally the
solvent-exposed polar substituent on the aryl group exhibited no
profound effect on the potency of the compounds and appeared to
be a site amenable for modifications to alter the properties of the
compound. As indicated by the brain/plasma concentration ratio,
the efforts to restrict the brain penetration of the compounds by
increasing the polar surface area with the incorporation of polar
basic and neutral aryl substituents at C-3 was unsuccessful (24,
26 and 30). However, compounds with a C-3 aryl group bearing
acid substituents (31 and 32) exhibited exquisite potency for
PDE10a with little to no blood-brain barrier penetration.
Similarly various acid isosteres11 such as acyl sulfonamides (34
and 35), hydroxytriazole 36, dihydroxyisoxazole 37 and
hydroxyoxadiazole 38 also showed excellent inhibitory activity
towards PDE10A as well as peripheral restriction.
Figure 5. Decomposition of 2-oxymethyl quinolyl imidazolopyridazine HCl
salt
As the poor stability of these compounds was a
significant concern, we chose to explore potential replacement
linkers that would produce analogues with better stability and
potency. Molecular modeling studies suggested that saturated as
well as unsaturated two atom linkers might be able to serve as
potential replacements of the vulnerable oxymethyl tether (Fig.
3).
The evaluation of alkene and alkyne linker containing
compounds for potential chemical issues revealed that
compounds with alkene linked quinoline underwent photo-

induced cis-trans isomerization in solutions. The alkyne-linked
quinolone containing compounds showed an adduct formation
with glutathione in vitro,12 indicating the potential for
compounds with the diaryl alkyne structure to form reactive
metabolites. These observations warranted further exploration of
the potential linkers for the attachment of the quinoline.
iodo cyclobutane 17 and 2-iodoquinoline was utilized for the
synthesis of 18 as a cis/trans mixture. The hydroxy cyclobutane
ester 16 was employed as the starting material in this synthetic
sequence and was converted to compound 17 via a two-step
process. The alcohol was first converted to the tosylate and then
displaced with iodide to yield the target 17. The morpholine
substituent was installed by reacting dibromo compound 21 with
excess morpholine. The remaining Br was then removed under
reductive conditions to obtain 22. The C-3 aryl group was then
attached as described in Scheme 2.
Table 1. PDE10a activity and brain penetration of imidazo[1,2-b]pyridazine
analogues
Scheme 3. Synthesis of the cyclobutane linked quinolones
Cpd.
24
R1
L
hPDE10a IC50 Brain/plasma
(nM)
ratio at 2 ha
CH3
123
0.45
25
26
27
-CH2O-
-CH2S-
NA
20
NA
0.82
NA
Reagents and conditions: (a) (i) TsCl, pyridine, 0 °C rt, 18 h; (ii) NaI,
MEK, 100 °C (microwave), 4 h (b) (i) Li, naphthalene, THF, ZnCl2; (ii) 2-I-
quinoline, Pd2(dba)3, trifurylphosphine, rt, 12 h; (c) 1M NaOH, EtOH, rt, 12
h; (d) (i) (COCl)2/cat. DMF, DCM, 0 °C rt, 30 min.; (ii) 2M TMSCHN2 in
hexanes, CH3CN, rt, 1 h; (iii) 33% HBr/HOAc, 0 °C rt, 30 min.; (e) 4,6-
dibromopyridazin-3-amine, DMF, rt, 72 h.; (f) (i) morpholine, DIEA, CH3CN
, 60 °C, 3 h; (ii) 10% Pd/C, HCOONH4, THF, MeOH, 60 °C, 3 h; (g) ArBr,
Pd(OAc)2, Ph3P, KOAc, DMAc, 110 °C, 22 h.
21.4
28
29
30
-CH2CH2-
-CH2S-
20.4
3.0
NA
NA
0.31
13.8
The evaluation of the 1,3-trans cyclobutane linked
quinoline analogues with acidic substituents on the C-3 position
in the PDE10A inhibition assay as well as brain permeability
studies revealed that these analogues were also excellent
inhibitors of PDE10a with no appreciable central penetration
(Table 1: 39, 40 and 41).
31
32
33
1.5
1.2
4.4
0
-CH2CH2-
0
0.02
34
35
2.2
2.1
0
After a successful campaign to identify peripherally
restricted, selective, potent PDE10a inhibitors with acceptable
chemical properties, evaluation of efficacy as insulin
secretagogues was undertaken. Compound 31 was chosen as a
suitable candidate for further profiling and initial efficacy studies.
It was equipotent in both hPDE10a and rPDE10a assays (Table
2). It showed well over 200-fold selectivity for all PDE subtypes
tested. In the recombinant cytochrome P450 (CYP) inhibition
assay, 31 had no significant inhibitory activity against all CYP
isoforms tested. The compound also had robust stability in
human, rat, dog, mouse and cynomolgus monkey liver
microsomal stability assays. In routine cardiovascular safety
screens, 31 exhibited no hERG binding and there were no
noticeable adverse effects in anesthetized guinea pig
cardiovascular endpoints.
0.01
36
37
7.4
8.5
0
0.01
38
3.3
0
39
40
0.6
3.2
0
0.02
41
2.4
0
NA- not available
a. Perfusion or non-perfusion of the brain did not affect the brain/ plasma
ratio.
Table 2: Profile of 31
rPDE10a (IC50, nM) = 2.0
hPDE10a (IC50, nM) = 2.0
In Vitro Profile
Selectivity
Since the selectivity pocket of the PDE10a binding site
can accommodate geometrically diverse linkers (Fig. 3), a 1,3-di
substituted cyclobutane linker that has close geometrical shape to
disubstituted acetylene was next exploited as a potential
acetylene linker replacement.
hPDE1b= 6.6 M, hPDE 2a = 5.9 M, hPDE
3b = 6.6 M, hPDE 4D= 4.0 M, hPDE 5a =
5,4 M, hPDE7a = 4.2 M, hPDE9a> 10 M,
hPDE = 3.0 M.
CYP Inhibition
Rat PK
Recombinant CYPs (IC50, M): 3A4, 2C9,
2C19, 2D6, 1A2 > 10.
Scheme 3 illustrates the synthesis of cyclobutane-tethered
quinoline analogues. The key step in this synthesis was the
cyclocondensation of the -bromoketone 20 with 4,6-
dibromopyridazin-3-amine to construct the core ring structure.
The bromo ketone 20 was synthesized by the action of HBr on in
situ generated diazoketone derived from the carboxylic acid 19.
The Negishi coupling of organozinc reagent prepared from the
F = 44%, Cl = 3.3 mL/min/kg, T1/2 iv = 6.1 h,
Cmax = 2993 ng/ mL, Vss = 0.47 L/ kg
A rat pharmacokinetic study at 10 mg/kg (Table 2)
showed 31 to display a moderate volume of distribution (0.47

L/kg) compared to total body water (0.688 L/kg). The compound
had a reasonable half-life (ca. 6 h) with low clearance and 44%
oral bioavailability.
References and notes
1.
Chappie, T. A.; Helal, C. J.; Hou, X. J. Med. Chem. 2012, 55(17),
7299.
Figure 6. Insulin response to known insulin secretagogues and compound 31
in human islets
2.
3.
K. U. Leuven Research and Development. WO2005/120474
Cantin, L.D.; Magnuson, S.; Gunn, D.; Barucci, N.; Breuhaus, M.;
Bullock, W.H.; Burke, J.; Claus T.H.; Daly, M.; Decarr, L.; Gore-
Willse, A.; Hoover-Litty, H.; Kumarasinghe, E.S.; Li, Y.; Liang,
S.X.; Livingston, J.N.; Lowinger, T.; Macdougall, M.; Ogutu,
H.O.; Olague, A.; Ott-Morgan, R.; Schoenleber, R.W.;
Tersteegen, A.; Wickens, P.; Zhang, Z.; Zhu, J.; Zhu, L.; Sweet,
L.J. Bioorg. Med. Chem. Lett. 2007, 17, 2869.
4.
5.
Janssen Pharmaceutica NV. WO2011/051342 .
Black S.C.; Gibbs E.M.; McNeish J.D. WO 2005/041972 2005.
6. Verhoest, P. R.; Chapin, D. S.; Corman, M.; Fonseca, K.; Harms,
J. F.; Hou, X.; Marr, E. S.; Menniti, F. S.; Nelson, F.; O’Connor,
R.; Pandit, J.; Proulx-LaFrance, C.; Schmidt, A. W.; Schmidt, C.
J.; Suiciak, J. A.; Liras, S. J. Med. Chem. 2009, 52, 5188.
7.
Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.;
Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley,
M.; Perry, J. K.; Shaw, D. E,; Francis, P.; Shenkin, P. S. J. Med.
Chem., 2004, 47 (7), 1739.
8.
9.
Ramasamy, A. K.; Balasubramaniam, V.; Mohan, K. E-Journal of
Chemistry, 2010, 7(3), 1066.
Ryabukhin, S. V.; Plaskon,A. S.; and Volochnyuk, D. M. J.
Comb. Chem. 2007, 9, 1073-1078.
The ability of 31 to induce the insulin secretion from
isolated rat islets in vitro was also evaluated under both low
glucose (3 mM) and high glucose (12 mM) levels at 0.1, 0.3, 1
and 3 M concentrations. Compound 31 showed no noteworthy
efficacy in inducing insulin secretion from rat islets.
10. Zhou, Xiaomeng, Z.; Xiaokang, L.; Wei, Z.; Junmin, Z. Tet. -
Lett. 2014, 55(37), 5137-5140.
11. X. Ballatore,C.; Huryn,D. M.; Smith, III A. B. ChemMedChem.
2013, 8, 385 – 395
12. Singh, R.; Silva Elipe., M. V.; Pearson, P. G.; Arison, B. H.;
Wong, B. K.; White, R.; Yu, X.; Burgey, C. S.; Lin, J. H.; Baillie,
T. Chem. Res. Toxicol. 2003, 16, 198−207.
In addition, in human islets that displayed robust
secretion to several known insulin secretagogues (glucose, KCl,
arginine, sulphonylurea (glibenclamide), and a GLP-1 receptor
agonist, compound 31 resulted in a mild increase in insulin
release at 1M (Figure 6).
Compound 31 was evaluated in an oral glucose
tolerance test (oGTT) in Sprague Dawley rats fasted for 6 h and
16 h at 3, 10 and 30 mg/kg dose levels, administered 3 h prior to
the oral dose of 2 g/kg of glucose using 10 mg/kg sitagliptin as a
positive control. Compound 31 was also tested at 5, 10 and 20
mg/kg oral doses given 3 h prior to the administration of 1 g/kg
dose of glucose in ob/ob mice in an oGTT study. In both studies
31 demonstrated unremarkable efficacy in lowering blood
glucose levels up to 2 h after glucose administration.
3
However
a
report has previously
described the identification of a class of
peripherally-restricted quinolone-based
PDE10a inhibitor leads, as insulin
secretagogues. One of the optimized
compounds (42) was reported to show
1.4-fold insulin secretion over the control
(8 mM glucose and 0.3 M forskolin) in
a dispersed rat islet assay. In vivo, 42 was also efficacious,
causing a 20.4% glucose AUC reduction in a rat intraperitoneal
glucose tolerance test at 1 mg/kg without causing hypoglycemia
and with a measurable increase in insulin.
In conclusion, a novel series of potent PDE10a
inhibitors exhibiting excellent peripheral restriction and sub-type
selectivity has been identified. Unfortunately, these compounds
did not exhibit the anticipated glucose lowering effect either in
vitro or in vivo. At the present time there is no conclusive
explanation for the lack of the predicted pharmacodynamic effect
of the described PDE10a inhibitors given the former report3. In
addition, a recent article1 has also raised the question of the
validity of PDE10a inhibitors as therapeutic agents for the
treatment of metabolic disease due to the lack of follow-up
literature reports related to the patents claiming the utility of
PDE10a inhibitors in for these indications. We agree with this
notion, and have diminished interest in PDE10a inhibitors as a
class of therapeutics of value for the treatment of Type 2
diabetes.