Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

Article abstract of DOI:10.1016/j.bmcl.2014.04.087

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies foc

Full text of DOI:10.1016/j.bmcl.2014.04.087

Accepted Manuscript
Discovery and SAR of a novel series of metabotropic glutamate receptor 5 pos-
itive allosteric modulators with high ligand efficiency
Mark Turlington, Meredith J. Noetzel, Thomas M. Bridges, Paige N. Vinson,
Thomas Steckler, Hilde Lavreysen, Claire Mackie, José M. Bartolomé-Nebreda,
Susana Conde-Ceide, Han Min Tong, Gregor J. Macdonald, J. Scott Daniels,
Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley,
Shaun R. Stauffer
PII:
S0960-894X(14)00444-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.04.087
BMCL 21580
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Accepted Date:
24 March 2014
23 April 2014
Please cite this article as: Turlington, M., Noetzel, M.J., Bridges, T.M., Vinson, P.N., Steckler, T., Lavreysen, H.,
Mackie, C., Bartolomé-Nebreda, J.M., Conde-Ceide, S., Tong, H.M., Macdonald, G.J., Scott Daniels, J., Jones,
C.K., Niswender, C.M., Jeffrey Conn, P., Lindsley, C.W., Stauffer, S.R., Discovery and SAR of a novel series of
metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency, Bioorganic &
Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.04.087
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Discovery and SAR of a novel series of
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metabotropic glutamate receptor 5 positive allosteric
modulators with high ligand efficiency
Mark Turlington, Meredith J. Noetzel, Thomas M. Bridges, Paige N. Vinson, Thomas Steckler, Hilde Lavreysen, Claire
Mackie, José M. Bartolomé-Nebreda, Susana Conde-Ceide, Han Min Tong, Gregor J. Macdonald, J. Scott Daniels, Carrie
K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley and Shaun R. Stauffer

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery and SAR of a novel series of metabotropic glutamate receptor 5
positive allosteric modulators with high ligand efficiency
Mark Turlington a,b,c,d, Meredith J. Noetzel a,b,c, Thomas M. Bridges a,b,c, Paige N. Vinson a,b, c, Thomas
Stecklere, Hilde Lavreysene, Claire Mackief, José M. Bartolomé-Nebredag, Susana Conde-Ceideg, Han Min
Tongg, Gregor J. Macdonalde, J. Scott Daniels a,b,c, Carrie K. Jones a,b,c, Colleen M. Niswendera,b,c, P. Jeffrey
Conna,b,c, Craig W. Lindsleya,b,c,d and Shaun R. Stauffera,b,c,d*
aDepartment of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
bVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
cVanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA
dDepartment of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
eNeuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340, Beerse, Belgium
fDiscovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340, Beerse, Belgium
gNeuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007-Toledo, Spain
*To whom correspondence should be addressed: shaun.stauffer@vanderbilt.edu
ARTICLE INFO
ABSTRACT
We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5)
positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-
a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-
amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly
potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one
(11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In
addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising
lead properties and exploration of alternative core heterocycles, linkers, and ketone
replacements, oxidative metabolism and in vivo clearance remained problematic for the series.
Article history:
Received
Revised
Accepted
Available online
Keywords:
metabotropic glutamate receptor 5, mGlu5, positive
allosteric modulator (PAM)
2014 Elsevier Ltd. All rights reserved.
The pursuit of positive allosteric modulators (PAMs) of mGlu5 as
a novel and promising therapeutic approach to treat cognitive
deficits in schizophrenia has been stimulated by evidence from
several antipsychotic and cognitive animal models.1-6 During a
decade in which industry and academic discovery groups began
pursuing optimal molecules, over eight chemically diverse brain
penetrant chemotypes with in vivo efficacy in preclinical models
have been reported, beginning with CDPPB,7 ADX-47273 (2),8,9
acetylenes VU0360172 (1)10 and LSN2463359,11-13 piperazines
VU0364289,14 DPFE (4),15 CPPZ;16 ether VU0404251 (3),17 and
triazole LSN2814617 (Figure 1).12 Recent findings from Merck-
Addex and these laboratories have unveiled a target-mediated
CNS adverse-effect (AE) liability, driven by excessive PAM
cooperativity18 or allosteric agonism,19,20 respectively, suggesting
that PAMs with lower cooperativity and devoid of allosteric
agonism may be preferable for obtaining an improved therapeutic
index.
More recently, we disclosed phenoxy-based tool
compounds derived from
a
dihydrothiazolopyridone21 and
napthyridinone22 series; these compounds include PAMs with
low to moderate efficacy. Although CNS disposition was
excellent, optimized modulators maintained relatively high
clearance in rat and dog and were notably less potent relative to
picolinamide-based acetylenic PAMs, which readily achieve sub-
100 nM in vitro potency.
Figure 1. Representative mGu5 PAMs with amide and non-amide hydrogen-
bond acceptor (HBA) pharmacophores.
As part of an effort to examine the common amide motif present
within chemotypes 1-4, we were interested in determining if

bicyclic acetylenic-based ketone 5 and alcohol 6 reported by
Merz23 as potent mGlu5 PAMs (rat mGlu5 EC50 = 34 and 180
nM, respectively) would serve as an alternate hydrogen-bond
acceptor (HBA) pharmacophore within one of our non-acetylene
ether-based scaffolds. Incorporation of a chiral hydroxyl moeity
was particularly attractive as a means to add sp3 character as well
as an opportunity to carry a hydrogen bond donor to enhance
aqueous solubility, a structural motif presently rare in mGlu5
PAMs. Although encouraged at the outset, we were also
cognizant of recent structure-activity relationships (SAR) in a
picolinamide acetylene chemotype demonstrating that hydroxyl
installation within an eastern amide either directly, or through
bioactivation, uncovered an unexpected allosteric agonist activity
at mGlu5, a pharmacological profile associated with epileptiform
activity and a target mediated AE liability.19,20,24 To test the
viability of alternate HBA pharmacophores fragments like those
found within the Merz tetralone scaffolds, we utilized a recently
developed 5,6-bicyclic pyrazole lactam nucleus25 as a template to
test this hypothesis. To this end we focused on target 11, which
was envisioned to be synthesized via a Dieckmann condensation
followed by Krapcho decarboxylation from key intermediate 9.
Synthesis of the initial proof-of-concept target ketone 11 began
with prepearation of known pyrazole ester 8 (Scheme 1).
Subjection of phenoxyacetone to sodium ethoxide and addition of
the resulting enolate to diethyl oxalate yielded -diketone 7.
Condensation with hydrazine afforded the desired pyrazole ester
8, which was carried forward without purification.
Unfortunately, alkylation of 8 with ethyl 4-bromobutyrate and
NaH in THF at 0 C afforded exclusively undesired regioisomer
9’. A screen of bases and solvents (LiOH, KOH, K2CO3,
Cs2CO3, KOtBu, LHMDS; MeCN, toluene, DMSO, DMF)
revealed that K2CO3 in DMF were optimal for alkylation of 8,
yielding in a 3:1 mixture of regioisomers 9 and 9’ (69% isolated
yield 9). With diester 9 in hand, Dieckmann condensation
(KOtBu, toluene, reflux) successfully afforded bicylic -ketoester
10 in 81% yield. LiCl mediated Krapcho decarboxylation
provided access to ketone 11 in 77% yield, and was found to be
more efficient than H2SO4 mediated decarboxylation (62% yield,
24 h).
yield). Ketone analogs bearing eastern aryl groups were accessed
via Pd[P(t-Bu)3]2 catalyzed -arylation with aryl bromides in 43-
85% yield.26 However, -arylation with substrate 11 under these
and a variety of standard conditions exhibited a limited substrate
scope and was incompatible with heteroaryl halides.
In parallel, the ketone moiety was replaced with alkyl ethers to
test the impact of an ether hydrogen bond acceptor and the effect
of steric bulk in the northern region of the molecule. Ether
analogs 13 were prepared by carbonyl reduction of 11 with
NaBH4 (83% yield) followed by treatment with NaH in DMF and
addition of alkyl halides. A limited number of analogs were also
prepared from ketone analogs 12 bearing eastern substituents to
test the effect of steric bulk at the eastern and northern regions of
the scaffold.
Scheme 2. Reagents and conditions: (a) NaH, THF, 0C; then RI or RBr, rt 3
h, 10-75% (b) ArBr, Pd(tBu3P)2, K3PO4, DMA, 80 C, 18 h, 43-85% (c)
NaBH4, MeOH, 0 C, 1 h, 65-80%; (d) NaH, DMF, 15 min; then RI or RBr 0
C to rt, 16 h, 45-60%, (e) RMgBr, THF, -78 C to rt, 50-83%; (f) TMSCF3,
TBAF (catalytic), THF, rt, 24 h, 54%; (g) TiCl4, RNH2, CH2Cl2, rt, 18 h; then
NaCNBH3, MeOH, rt, 30 min, 42-90%. All compounds were purified by
silica-phase automated chromatography or preparative RP-HPLC.
Table 1. Structures and activities of 11 and ketone analogs 12.a
Scheme 1. Reagents and conditions: (a) Na, EtOH, 0 C to rt, 2 h, 45%; (b)
H2NNH2, EtOH, 80 C, 1.5 h; (c) ethyl 4-bromobutyrate, K2CO3, DMF, rt, 18
h, (3:1 ratio 9:9’), 69% 9 over 2 steps; (d) KOtBu, toluene, rt to reflux, 1 h,
81%; (e) LiCl, H2O, DMSO, 115 C, 10 h, 77%.
With access to dihydropyrazolopyridin-one 11, a number of
analogs were synthesized to test the effect of hydrogen bond
acceptors and donors in the northern region of the molecule and
to probe the effect of steric bulk in the northern and eastern
regions. To this end, a variety of keto-analogs with eastern
substituents (12), alkyl ether analogs (13), alcohol analogs (14),
and amine analogs (15) were prepared (Scheme 2). Eastern alkyl
ketone analogs 12 were synthesized via enolate formation of 11
with NaH in THF followed by addition to alkyl halides (10-75%

Analogs containing northern hydrogen bond donors were pursued
as shown in Scheme 2 through preparation of secondary and
tertiary alcohols and secondary amines. Tertiary alcohols 14
were accessed by Grignard addition to ketone 11 in 50-83% yield
or reaction with Ruppert’s reagent (54% yield). Amine analogs
15 were synthesized via TiCl4 mediated reductive amination (42-
90% yield). In addition, selected analogs bearing tertiary amines
were prepared.
micromolar modulator. Analogs bearing eastern substituents in
addition to the northern alkyl ether were synthesized and methyl
ester 13b, bearing geminal -methyl groups, displayed increased
potency (796 nM) over des-methyl analog 13a; however, the
overall poor potency of alkyl ether analogs 13a-e suggested a
preference for the ketone moiety as a hydrogen bond acceptor at
the allosteric binding site.
Evaluation of tertiary alcohols 14a-g (Table 2), representing a
desirable moiety to enhance physicochemical properties, revealed
a similar loss of potency upon modification of the ketone as no
analogs within the series achieved sub-micromolar potency.
Direct comparison of ketone 11 to secondary alcohol 14a
revealed a drastic loss of potency (15-fold). This was a
surprising result given the minimal decrease in potency reported
within the Merz tetralone acetylene series upon reduction of the
ketone to the secondary alcohol (Figure 1, ~5-fold from 5 to 6).23
The introduction of steric bulk at R2 slightly improved potency
(14c, 14f-g), while incorporation of the trifluoromethyl moiety
(14e) further diminished activity. In contrast to picolinamide
acetylenes containing a chiral hydroxyl moiety no agonist
activity was observed for the more active quaternary carbinols
(e.g. 14c and 14g); however, PAM potency is generally two
orders of magnitude lower.24
The SAR are shown in Tables 1 – 3. Ketone 11 and analogs 12
are shown in Table 1, with the dihydropyrazolopyridin-one
scaffold gratifyingly affording a number of highly potent analogs
with moderate to high efficacy (52-96% Glu max). Parent ketone
11 exhibits excellent potency (129 nM); at a MW = 242,
containing 18 non-hydrogen atoms, and a cLogP of 1.7, 11
displays excellent ligand efficiency metrics with an LE and LELP
of 0.52 and 3.2, respectively.27 In both human and rat mGlu
selectivity panels, 11 was highly selective for mGlu5 (mGlu1-3
,
6-8
> 10 M). The presence of alkyl and aryl groups in the eastern
region of the scaffold were well tolerated and often led to modest
increases in potency. In particular, introduction of -aryl groups
(12c, 12d), and spirocycle 12f improved potency 3-fold in
relation to parent ketone 11. These results suggest that the
incorporation of some steric bulk in the eastern region of the
molecule may be beneficial. However, the greatly reduced
potency of dibenzyl analog 12g and the diminished activity of di-
substituted analogs 12h and 12i demonstrate limited steric bulk is
required for optimal potency.
In parallel, analogs bearing northern amines were examined
(Table 3, 15a-n). While still possessing decreased potency
relative to ketone analogs 11, these analogs were found to afford
better results than ether analogs 13 and alcohol analogs 14.
Primary amine 15a was only weakly active, but incorporation of
alkyl, aryl, and benzyl groups were beneficial for potency.
Furthermore, both secondary and tertiary amines were found to
be tolerated. Although undesirable, the potency displayed by
Table 2. Structures and activities of ether analogs 13 and tertiary
alcohols 14.a
aniline 15e (269 nM) presented a promising starting point.
A
number of benzyl amine analogs were pursued as aniline
replacements, with benzyl amine congener 15f displaying a 2-
fold loss in potency relative to 15e. Methylation to yield tertiary
amine 15h did not significantly alter potency, but introduction of
geminal methyl groups  to the amine (15g) greatly reduced
potency, demonstrating that increased steric bulk is not well
tolerated within amines of type 15. The 3-fluorobenzyl amine
15i and 4-methoxybenzylamine 15l were identified as equipotent
analogs versus aniline 15e.
We next evaluated the DMPK profiles of selected analogs.
While ketone 11 and keto analogs 12 represented the most
potent analogs, we were concerned that the carbonyl could be a
metabolic liability. In a hepatic microsomal intrinsic clearance
assay ketone 11 displayed moderate to high in vitro metabolism
with predicted hepatic clearance (CLHEP) = 46.1 mL min-1 kg-1 in
rat and 15.2 mL min-1 kg-1 in human. Plasma protein binding
experiments revealed that 11 was highly unbound (21% unbound
in rat plasma, 23% unbound in human plasma,) and stable in
plasma from both species (4 hr incubation; 37 °C). Analysis of
the inhibition of the major cytochrome P450 (CYP) enzymes
demonstrated that 11 has moderate inhibitory activity at 1A2 (6.2
M), with no activity observed against the other major CYPs
tested (2C9, 2D6, 3A4). Dimethyl analog 12e displayed higher
predicted clearance, near hepatic blood flow (64.4 mL min-1 kg-1
in rat and 17.6 mL min-1 kg-1 in human), with a reduced yet
attractive fraction unbound (7% unbound in rat plasma, 10%
unbound in human plasma). Like PAM 11, 12e displayed modest
inhibitory activity at 1A2 (7.3 M). -Aryl congener 12c, the
most potent mGlu5 PAM from this study as a racemic mixture
Encouraged by these results, we replaced the ketone hydrogen
bond acceptor with alkyl ethers to ascertain the effect of this
hydrogen bond acceptor and to determine whether steric bulk
could be tolerated in the northern region of the scaffold (Table 2,
13). This modification proved to be detrimental, as ether
derivatives 13 displayed a greatly reduced potency in comparison
to ketone 11, with benzyl ether 13e representing the only sub-
(rat EC50 = 35 nM), was rapidly turned over in vitro (CLHEP
=
61.6 mL min-1 kg-1 in rat and 16.0 mL min-1 kg-1 in human) and
was moderate to highly bound across species (3.2% unbound in
rat plasma, 0.8% unbound in human plasma). The high in vitro

metabolic turnover for the series was ultimately confirmed in a
rat PK study (0.2 mg/kg, intravenous cassette paradigm, male
Sprague-Dawley, n = 2) using PAM 12c. As expected, 12c
proved to be a highly cleared compound in vivo with super
hepatic clearance (rat CLp = 120 mL min-1 kg-1).
bearing eastern substituents (17, 18) and benzyl amine derivative
19 surprisingly regained activity, though potency was slightly
diminished in comparison with their respective phenoxy
congeners.
Given the poor DMPK profile of the keto analogs, benzylamine
analog 15f was next profiled in order to determine if replacement
of the carbonyl with the secondary amine might afford improved
metabolic stability. Although PAM 15f maintained reasonable
fraction unbound (fu = 0.02 human plasma, fu = 0.03 rat plasma),
15f and other members in the amine series were highly
metabolized in vitro (15f, CLHEP = 68.1 mL min-1 kg-1 rat, 18.8
mL min-1 kg-1 human).
Table 3. Structures and activities of amine analogs 15.a
Figure 2. Benzyloxy and thiazole ketone analogs.
Once again, the metabolic profiles remained problematic (16-18,
CLHEP > 55 mL min-1 kg-1 rat, >13 mL min-1 kg-1 human) and
metabolic soft-spot analysis in a related series suggested
oxidative debenzylation was likely a contributing factor. Based
on
our
recently
disclosed
1,3-azole
containing
tetrahydrobenzothiazole mGlu5 PAM scaffold,21 the alternative
5,6-bicyclic thiazole ketone 20 was prepared to examine the
effect on potency and metabolic stability relative to the pyrazole
5,6-bicyclic ring systems. Comparator thiazole 20 displayed only
a 3-fold reduction in potency versus 11; however, compound 20
was highly metabolized in vitro based upon predicted hepatic
clearance in human and rat (Figure 2). Lastly, unable to improve
the DMPK profile with either western ether or core variations, we
attempted a difluoro moiety as an alternate hydrogen bond
acceptor to replace the ketone. From ketone 11 difluoro
congener 21 was prepared in 43% yield via reaction with Deoxo-
Fluor at 40 C (Scheme 3). Interestingly the difluoro moiety
within 21 was tolerated, affording a PAM with moderate potency
(625 nM) and efficacy (52% Glu max); however, metabolic
instability remained an issue, ultimately proving to be a fatal flaw
throughout each of the series investigated despite having
promising ligand efficiency metrics.
Based on metabolic soft-spot analysis from related ether series
developed in our laboratories, oxidative metabolism of the
electron rich western phenoxy moiety was believed to be a major
contributor to the observed metabolic instability. In an effort to
address this suspected instability, we prepared a series of
benzyloxy analogs from 5-benzyloxy-2H-pyrazole-3-carboxylic
acid ethyl ester in a fashion analogous to the phenoxy analogs
shown in Scheme 1. The key benzyloxy comparators, activities,
and in vitro metabolism data are summarized in Figure 2.
Interestingly, the benzyloxy ketone 16, which differs from 11 by
virtue of the ether linker, was found to be inactive and
maintained a poor metabolic profile. Benzyloxy ketone analogs
Scheme 3. Reagents and conditions a: Deoxo-Fluor/CH2Cl2 (1:1), 40 C, 60
h, 43%.
In summary, we have developed a set of highly potent mGlu5
PAMs with high ligand efficiency, achieving potency comparable

to acetylene-based mGlu5 PAMs (12c, rat EC50 = 35 nM).6,10,25
Compounds were profiled in a rat mGlu5 cell line with low
receptor expression and in contrast to picolinamide-based-
acetylene mGlu5 modulators,25 agonism was not detected for
compounds within series 13-15 and compounds 17-21. DMPK
profiling demonstrated generally moderate to high fraction
unbound; however, metabolic instability proved to be an
insurmountable issue for these novel mGlu5 chemotypes. Studies
within 5,6-pyrazole bicyclics that retain an amide structural
element25 are ongoing and will be communicated in due course.
15. Gregory, K. J.; Herman, E. J.; Ramsey, A. J.; Hammond,
A. S.; Byun, N. E.; Stauffer, S. R.; Manka, J. T.; Jadhav,
S.; Bridges, T. M.; Weaver, C. D.; Niswender, C. M.;
Steckler, T.; Drinkenburg, W. H.; Ahnaou, A.; Lavreysen,
H.; Macdonald, G. J.; Bartolome, J. M.; Mackie, C.;
Hrupka, B. J.; Caron, M. G.; Daigle, T. L.; Lindsley, C.
W.; Conn, P. J.; Jones, C. K. J Pharmacol Exp Ther 2013,
347, 438-57.
16. Spear, N.; Gadient, R. A.; Wilkins, D. E.; Do, M.; Smith, J.
S.; Zeller, K. L.; Schroeder, P.; Zhang, M.; Arora, J.;
Chhajlani, V. Eur J Pharmacol 2011, 659, 146-54.
17. Manka, J. T.; Vinson, P. N.; Gregory, K. J.; Zhou, Y.;
Williams, R.; Gogi, K.; Days, E.; Jadhav, S.; Herman, E.
J.; Lavreysen, H.; Mackie, C.; Bartolome, J. M.;
Macdonald, G. J.; Steckler, T.; Daniels, J. S.; Weaver, C.
D.; Niswender, C. M.; Jones, C. K.; Conn, P. J.; Lindsley,
C. W.; Stauffer, S. R. Bioorg Med Chem Lett 2012, 22,
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Acknowledgments
Vanderbilt Center for Neuroscience Drug Discovery (VCNDD)
research was supported by grants from Janssen, The
Pharmaceutical Companies of Johnson & Johnson and in part by
the NIH (NS031373, MH062646).
18. Parmentier-Batteur, S.; Hutson, P. H.; Menzel, K.; Uslaner,
J. M.; Mattson, B. A.; O'Brien, J. A.; Magliaro, B. C.;
Forest, T.; Stump, C. A.; Tynebor, R. M.; Anthony, N. J.;
Tucker, T. J.; Zhang, X. F.; Gomez, R.; Huszar, S. L.;
Lambeng, N.; Faure, H.; Le Poul, E.; Poli, S.; Rosahl, T.
W.; Rocher, J. P.; Hargreaves, R.; Williams, T. M.
Neuropharmacology 2013.
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