Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABAAα2/α3 binding site agonists for the treatment of anxiety disorders

Article abstract of DOI:10.1021/jm051065l

A series of high-affinity GABA_A agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA _Aα2 and -α3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.

Full text of DOI:10.1021/jm051065l

J. Med. Chem. 2006, 49, 35-38
35
Imidazo[1,2-a]pyrimidines as Functionally
Selective and Orally Bioavailable GABAAr2/r3
Binding Site Agonists for the Treatment of
Anxiety Disorders
Simon C. Goodacre,* Leslie J. Street,* David J. Hallett,
James M. Crawforth, Sarah Kelly, Andrew P. Owens,
Wesley P. Blackaby, Richard T. Lewis, Joanna Stanley,
Alison J. Smith, Pushpinder Ferris, Bindi Sohal,
Susan M. Cook, Andrew Pike, Nicola Brown,
Keith A. Wafford, George Marshall, Jose´ L. Castro, and
John R. Atack
Departments of Medicinal Chemistry, Biochemistry, and
Pharmacology, Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park, Eastwick Road,
Harlow, Essex CM20 2QR, U.K.
Optimization of these leads gave the GABAAR2/3 functionally
selective agonists 310,15,16 and 417,18 as nonsedating anxiolytics
in animal models, from which triazolopyridazine 4 was chosen
as a clinical candidate. Second generation compounds were
targeted that were structurally distinct with good oral bioavail-
ability in rat and dog and with higher functional selectivity for
the GABAAR2 and R3 subtypes than 4.
ReceiVed October 21, 2005
Abstract: A series of high-affinity GABAA agonists with good oral
bioavailability in rat and dog and functional selectivity for the
GABAAR2 and -R3 subtypes is reported. The 7-trifluoromethylimida-
zopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are
anxiolytic in both conditioned and unconditioned animal models of
anxiety with minimal sedation observed at full BZ binding site
occupancy.
The 7-methylimidazopyridine lead 8a19 was identified as a
novel GABAA ligand and has some structural similarity to the
high-efficacy GABAAR3 agonist NS-2710.20 Compound 8a had
similar binding affinity for the GABAAR3 subtype as diazepam
but was essentially a BZ antagonist (Table 1). With the aim of
identifying compounds with higher efficacy for the GABAAR2/3
subtypes, alternative aryl groups for the pyridine ring of 8a were
targeted. Compounds were prepared by Suzuki coupling of the
boronate ester 7 with a range of aryl bromides (Scheme 1).
Compound 7 was prepared in four steps from 3-bromo-7-
Inhibitory neurotransmission in the central nervous system
is mostly mediated through GABAA receptors by the binding
of the agonist γ-aminobutyric acid (GABA).1,2 These receptors
are ligand-gated chloride ion channels that, in addition to binding
GABA, are the site of action of a number of allosteric
modulators including barbiturates, neurosteroids, loreclezole,
anesthetics, ethanol, and benzodiazepines (BZs).3 Purification,
sequencing, and cloning of the GABAA receptor and its
composite subunits has identified 16 subunits arranged within
seven families (R1-R6, â1-â3, γ1-γ3, δ, ꢀ, π, and θ).4
Expression of recombinant GABAA receptors shows that at least
one R, one â, and one γ (or δ or ꢀ) subunit are required to
form a pentameric, functional GABA-gated chloride ion
channel.4-7 The benzodiazepine binding site occurs at the
interface of the R and γ subunits and the combination of R and
γ subunits strongly influences both the affinity and efficacy (i.e.,
the ability to modulate GABA-induced chloride ion flux) of
ligands for the benzodiazepine binding site.8 Thus, it has been
shown that the major benzodiazepine sensitive GABAA receptor
subtypes in brain are those that contain â and γ2 subunits in
conjunction with either an R1, R2, R3, or R5 subunit.5 Since
the γ2 is invariant, the benzodiazepine pharmacology of GABAA
receptors is dictated primarily by the R subunit present.5
Currently used BZ anxiolytics such as diazepam are nonse-
lective, high-efficacy agonists, and these compounds show
sedative, muscle-relaxant, and amnesic properties. By use of
transgenic mice with point mutations in the R subunit that render
the corresponding receptor insensitive to diazepam (while
retaining responsivity to GABA), it has been shown that GABAA
receptors containing an R1 subunit mediate the sedative/muscle
relaxant effects of BZs, whereas those containing an R2 or an
R3 subunit or both mediate anxiolytic and anticonvulsant
effects.9-11 There is also evidence that the R5 subunit is
associated with memory and learning and is not involved in
anxiety.12 We recently reported on the 1,2,4-triazolopyridazines
113 and 214 as moderately selective GABAAR3 agonists.
21
methylimidazopyridine 5. Binding affinities were measured
by inhibition of [3H]Ro15-1788 binding to human recombinant
GABAA receptor subtypes stably expressed in L(tk-) cells
containing either R1, R2, R3, or R5 subunits in combination
with â3 and γ2.22 The in vitro efficacy for most compounds
was measured on the same combination of GABAA receptor
subtypes using whole cell patch clamp electrophysiological
recordings in the presence of a submaximal (EC20) concentration
of GABA.23 Alternatively, efficacies were determined in the
same cell lines by measuring the modulation of 36Cl ion flux
produced by the EC20 concentration of GABA in the presence
of a concentration of 1000Ki of the test compound.24 The lead
imidazopyridine identified from Suzuki reactions with 7, the
2-cyanophenyl analogue 8b, had 4-fold higher affinity at
GABAAR3 compared with 8a and, most importantly, was a
GABAA agonist with functional selectivity for the GABAAR3
subtype over R1- and R5-containing GABAA receptors. Unfor-
tunately, compound 8b had low oral bioavailability (F ) 2%)
and moderate plasma clearance in rat (Clp ) 44 mL min-1
kg-1), so structural changes were sought to improve pharma-
cokinetics, including modification of the imidazopyridine ring.
A 10-fold increase in binding affinity for the GABAAR3 receptor
was realized by replacing the imidazopyridine ring of 8b with
an imidazo[1,2-a]pyrimidine ring to give 14a (Table 1).
Functional selectivity for GABAAR3 was maintained, and in
addition, 14a had significantly improved oral bioavailability in
rat (F ) 42%) and lower plasma clearance (13 mL min-1 kg-1
)
compared with 8b. Compound 14a, however, had <5% oral
bioavailability in dog with liver blood flow plasma clearance
(Clp ) 41 mL min-1 kg-1). In vitro metabolism studies using
liver microsomes identified the methyl group and central phenyl
ring of 14a as being major sites of oxidative metabolism in
dog, so structural changes to these groups to improve metabolic
stability were undertaken. The imidazo[1,2-a]pyrimidines 14a-k
* To whom correspondence should be addressed. Telephone: (+1279)
440400. Fax: (+1279) 440187. E-mail addresses: simon_goodacre@
merck.com; leslie_street@merck.com.
10.1021/jm051065l CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/02/2005

36 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Letters
Table 1. Binding Affinity and Efficacy for Imidazo[1,2-a]pyridines and Imidazo[1,2-a]pyrimidines at GABAA Receptor Subtypes
a Ki values for binding to the benzodiazepine sites of stably expressed human recombinant GABAA receptors with the composition Rxâ3γ2 (x ) 1, 2, 3,
or 5). Inhibition of the binding of 1.8 nM [3H]-Ro15-1788 was measured, and the concentration required to inhibit binding by 50% (IC50) was converted to
a Ki value according to the Cheng-Prussof equation. Data shown are mean values for three to six determinations. b Efficacy was measured at GABAA
receptors stably expressed in L(tk-) cells using whole cell patch clamp recording and represents the effect of the test compound on the current produced by
a submaximal concentration of GABA (EC20). c Modulation of 36Cl chloride ion flux in cells expressing â3γ2 and either R1 or R3 produced by a submaximal
concentration of GABA (EC20) in the presence of an approximate 1000Ki concentration of test compound. Values are the mean of at least seven independent
experiments. ND ) not determined.
Scheme 1a
Scheme 2a
a Reagents and conditions: (a) 3-methoxybenzeneboronic acid, Pd(PPh3)4,
DME, 2 N Na2CO3, reflux; (b) HBr, AcOH, reflux; (c) Tf2O, pyridine,
DCM, 0 °C to rt; (d) bis(pinacolato)diboron, PdCl2(dppf), dppf, KOAc,
1,4-dioxane, 80 °C; (e) Ar-Br, Cs2CO3, Pd(PPh3)4, DME, reflux.
a Reagents and conditions: (a) bis(pinacolato)diboron, PdCl2(dppf),
KOAc, 1,4-dioxane, 90 °C; (b) Ar-Br, Pd2(dba)3, PtBu3, KF, THF, rt to
50 °C; (c) SnCl2‚2H2O, EtOH; (d) NaNO2, 48% HBr, CuBr, 0-50 °C; (e)
bis(pinacolato)diboron, PdCl2(dppf), KOAc, 1,4-dioxane, 90 °C.
were prepared as shown in Schemes 2 and 3.25-29 The aryl
bromides 10a-i and boronate esters 11a-i required for Heck
reaction with imidazopyrimidines 13a-c or Suzuki couplings
with the 3-bromoimidazopyrimidine derivatives were prepared
according to Scheme 2. Bromides 9a-d were converted to the
boronate esters under Miyaura conditions and then coupled with
the desired aryl bromides using a Fu protocol, before reduction
with stannous chloride and conversion to the bromides 10a-i
by Sandmeyer reaction. A Miyaura reaction with bromides

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 37
Scheme 3a
a Reagents and conditions: (a) HC(OEt)3, BF3‚Et2O, CH2Cl2, -40 to 0
°C, then RCOCH3, EtiPr2N, -78 °C to rt; (b) 2-aminoimidazole hemisulfate,
NaOMe, EtOH, reflux; (c) ethyl vinyl ether, pyridine, CH2Cl2; (d) guanidine
hydrochloride, NaOH, EtOH; (e) BrCH2CH(OEt)2, 48% HBr, EtOH, reflux;
(f) 10, Cs2CO3, Pd(PPh3)4, 1,4-dioxane, reflux; (g) Br2, KBr, NaOAc,
MeOH, 0 °C; (h) 11, K3PO4, Pd(PPh3)4, DMA, 65 °C.
Figure 1. Efficacy of 14k at human GABAA receptor subtypes
expressed in L(tk-) cells measured by whole cell patch-clamp elec-
trophysiology: a indicates that data shown are mean ( SEM of four
to six separate concentration-response curves for each subtype as
shown; b indicates efficacy of 14k relative to the nonselective full
agonist chlordiazepoxide (relative efficacy ) 1).
Figure 2. (A) The anxiolytic effects of 14k in the rat elevated plus
maze test. The mean time (( SEM, n ) 18/group) spent on the open
arms (expressed as a percentage of the total time, 5 min, on the maze)
after 30 min pretreatment with vehicle (0.5% methyl cellulose, p.o.),
14k (0.3, 1, or 3 mg kg-1 p.o.), or chlordiazepoxide (CDZ, 5 mg kg-1
i.p.). The statistically significant differences between vehicle and drug-
treated groups were determined using ANOVA followed by Dunnett’s
post hoc tests: / indicates p < 0.05. (B) Occupancy of brain GABAA
receptor benzodiazepine binding sites by 14k in a subset of rats taken
after completion of the elevated plus maze trial as measured by
inhibition of the in vivo binding of [3H]-Ro15-1788. Occupancy was
10a-i gave the boronate esters 11a-i. The imidazopyrimidines
13a and 13b were prepared by reaction of the ketones 12a and
12b, respectively, with diethoxycarbenium fluoroborate followed
by treatment of the resultant keto-acetals with 2-aminoimidazole
under basic conditions. 7-Trifluoromethyl imidazo[1,2-a]pyri-
midine 13c was prepared in three steps from trifluoroacetic
anhydride and ethyl vinyl ether (Scheme 3).
dose-dependent with an ID50 of 0.8 mg kg-1
.
An alternative, metabolically stable replacement for the
methyl group of 8a and 14a was shown to be propan-2-ol as
represented by compounds 14j and 14k (Table 1). Compound
14k had selective efficacy for GABAAR3 over the GABAAR1
subtype (Table 1) with higher efficacy for GABAAR3 subtype
than the first generation compound 4 and 14g. The efficacy of
14k relative to the nonselective high-efficacy BZ agonist
chlordiazepoxide (CDP) is shown in Figure 1. Compound 14k
is a GABAAR1 antagonist relative to CDP and a partial agonist
on both the GABAAR2 (0.39 relative to CDP) and GABAAR3
(0.54 relative to CDP) subtypes. Compound 14k had good
The 7-trifluoromethylpyrimidine 14b had comparable binding
affinity to the methyl analogue 14a but was less functionally
selective for the GABAAR3 subtype (Table 1). In the 7-trifluo-
romethylimidazopyrimidine series, the effect of fluorine sub-
stitution around the central phenyl ring on GABAA binding
affinity, functional selectivity, and pharmacokinetics was ex-
plored. Substitution with fluorine was best tolerated at the
4-position, compound 14d, the 2-fluoro isomer 14c and 5-fluoro
isomer 14e losing 8-fold and 43-fold GABAAR3 binding affinity,
respectively. Substitution on the 2-cyanophenyl ring of 14d with
fluorine was tolerated at all positions though the 2-cyano-3-
fluorophenyl- (14f) and 2-cyano-5-fluorophenyl- (14h) ana-
logues have significant efficacy for GABAAR1-containing
receptors. The 2-cyano-4-fluorophenyl analogue 14g was func-
tionally selective for GABAAR3 and GABAAR2 (+20.3%) over
R1- and R5-containing GABAA receptors and had a comparable
efficacy profile to the lead 1,2,4-triazolopyridazine 4. Compound
14g had good pharmacokinetics in rat (F ) 53%; Clp ) 10.3
mL min-1 kg-1; t1/2 ) 7.3 h), dog (F ) 29%; Clp ) 2.9 mL
min-1 kg-1; t1/2 ) 32 h), and rhesus monkey (F ) 49%; Clp )
3.0 mL min-1 kg-1; t1/2 ) 13.4 h) with improved plasma half-
life compared to 4 (rat F ) 35%, t1/2 ) 1.4 h; dog F ) 53%;
t1/2 ) 1.5 h)17 and displaced [3H]-Ro15-1788 in an in vivo
binding assay used to measure central BZ binding site oc-
cupancy30 with an ID50 of 0.27 mg kg-1 p.o. and an EC50 of
7.6 ng mL-1 (19nM). Compound 14g was active in the rat
elevated plus maze assay, an unconditioned model of anxiety,31
at 1 mg kg-1 p.o. (91% BZ site occupancy) with no impairment
shown in the rat chain pulling assay, a test of sedation, at 30
mg kg-1 p.o.32
pharmacokinetics in rat (F ) 77%; Clp ) 9.1 mL min-1 kg-1
;
t1/2 ) 1.7 h) and dog (F ) 48%; Clp ) 8.2 mL min-1 kg-1; t1/2
) 0.7 h) with an ID50 of 0.84 mg kg-1 p.o. and an EC50 of 202
ng mL-1 (469 nM) in the rat in vivo binding assay. Compound
14k was active in the rat elevated plus maze assay (Figure 2)
at 3 mg kg-1 p.o. (78% BZ site occupancy) with no impairment
seen in the rat chain pulling assay at 30 mg kg-1 p.o. The
nonselective full BZ agonist CDP was effective at 5 mg kg-1
i.p. in the elevated plus maze, which equated to 30% BZ receptor
occupancy. Both 14g and 14k were anxiolytic in the squirrel
monkey conditioned emotional response test, a conditioned
model of anxiety, at 0.3 and 3 mg kg-1 p.o., respectively.15,33
On the basis of the GABAA efficacy profiles and pharma-
cokinetics of 14g and 14k, these compounds were chosen as
additional development compounds for the treatment of anxiety
disorders, 14g having a similar GABAA in vitro efficacy profile
to the first development compound 4 but with a plasma half-
life in preclinical species indicative of once a day dosing in
man and 14k having higher efficacy for the GABAAR3 subtype
relative to 4.

38 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Letters
(16) Scott-Stevens, P.; Atack, J. R.; Sohal, B.; Worboys, P. Rodent
Pharmacokinetics and Receptor Occupancy of a GABAA Receptor
Subtype Selective Benzodiazepine Site Ligand. Biopharm. Drug
Dispos. 2005, 26 (1), 13-20.
(17) Carling R. W.; Madin A.; Guiblin A.; Russell M. G. N.; Moore, K.
W.; Mitchinson A.; Sohal B.; Pike A.; Ragan I. C.; McKernan R.
M.; Quirk K.; Atack J. R.; Wafford K. A.; Marshall G.; Thompson
S. A.; Dawson G. R.; Ferris P.; Castro J. L.; Street L. J. 7-(1,1-
Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluo-
rophenyl)-1,2,4-triazolo[4,3-b]pyridazine: A Functionally Selective
GABA-A R2/R3-Subtype Selective Agonist which Exhibits Potent
Anxiolytic Activity but is Not Sedating in Animal Models. J. Med.
Chem. 2005, 48, 7089-7092.
(18) Atack J. R.; Marshall G. R.; Ferris P.; Cook S. M.; Sohal B.; Pike
A.; Sur C.; Mellilo D.; Bristow L.; Bromidge, F.; Ragan I. C.; Kerby
J.; Street L. J.; Carling R. W.; Wafford K. A.; Whiting P. J.; Dawson
G. R.; McKernan R. M. TPA023, A Subtype Selective GABAA
Receptor Partial Agonist is a Nonsedating Anxiolytic in Rodents and
Primates. J. Pharmacol. Exp. Ther., in press.
(19) Crawforth, J. M.; Goodacre, S. C.; Hallett, D. J.; Harrison, T.; Owens,
A. P.; Rowley, M.; Teall, M. R. Preparation of 3-Phenylimidazo-
[1,2-a]pyridines as Ligands for GABA receptors. World Patent WO
01/038326, 2001.
(20) Teuber, L.; Watjen, F.; Fukuda, Y.; Ichimaru, Y. (Neurosearch A/S,
Den.; Meiji Seika Kaisha, Ltd.) World Patent WO 99/19323, 1999.
(21) Hand, E. S.; Paudler, W. W. Imidazo[1,2-a]pyridines - Novel
Substitution Reactions. J. Org. Chem. 1976, 41 (22), 3549-3556.
(22) Hadingham, K. L.; Wingrove, P.; Le Bourdelles, B.; Palmer, K. J.;
Ragan, C. I.; Whiting, P. J. Cloning of cDNA Sequences Encoding
Human R2 and R3 γ-Aminobutyric AcidA Receptor Subunits and
Characterization of the Benzodiazepine Pharmacology of Recombi-
nant R1-, R2-, R3-, and R5-Containing Human γ-Aminobutyric acidA
Receptors. Mol. Pharmacol. 1993, 43, 970-975.
(23) Brown, N.; Kerby, J.; Bonnert, T. P.; Whiting, P. J.; Wafford, K. A.
Pharmacological Characterisation of a Novel Cell Line Expressing
Human R4â3γ GABAA Receptors. Br. J. Pharmacol. 2002, 136,
965-974.
(24) Smith, A. J.; Alder, L.; Silk, J.; Adkins, C.; Fletcher, A. E.; Scales,
T.; Kerby, J.; Marshall, G.; Wafford, K. A.; McKernan, R. M.; Atack,
J. R. Effect of R Subunit on Allosteric Modulation of Ion Channel
Function in Stably Expressed Human Recombinant γ-Aminobutyric
AcidA Receptors Determined Using 36Cl Ion Flux. Mol Pharmacol.
2001, 59, 1108-1118.
(25) Blackaby, W. P.; Castro Pineiro, J. L.; Chambers, M. S.; Goodacre,
S. C.; Hallett, D. J.; Jones, P.; Lewis, R. T.; MacLeod, A. M.; Maxey,
R. J.; Moore, K. W.; Street, L. J. Preparation of 3,7-Disubstituted
Imidazo[1,2-a]pyrimidines as Ligands for GABA Receptors. World
Patent WO 02/076983, 2002.
Supporting Information Available: Experimental procedures
and characterization of intermediates and final compounds. This
material is available free of charge via the Internet at http://
pub.acs.org.
References
(1) Young, A. B.; Chu, D. Distribution of GABAA and GABAB Receptors
in Mammalian Brain: Potential Targets for Drug Development. Drug
DeV. Res. 1990, 21, 161-167.
(2) Rabow, L. E.; Russek, S. J.; Farb, D. H. From Ion Currents to
Genomic Analysis: Recent Advances in GABAA Receptor Research.
Synapse 1995, 21, 189-274.
(3) Korpi, E. S.; Grunder, G.; Luddens, H. Drug Interactions at GABAA
Receptors. Prog. Neurobiol. 2002, 67, 113-159.
(4) (a) Luddens, H.; Korpi, E. R.; Seeburg, P. H. GABAA/Benzodiazepine
Receptor Heterogeneity: Neurophysiological Implications. Neurop-
harmacology 1995, 34, 245-254. (b) Stephenson, F. A. The
GABA-A Receptors. Biochem. J. 1995, 310, 1-9. (c) Whiting, P.
J.; McAllister, G.; Vasilatis, D.; Bonnert, T. P.; Heavens, R. P.; Smith,
D. W.; Hewson, L.; O’Donnell, R.; Rigby, M. R.; Sirinathsinghji,
D. J. S.; Marshall, G.; Thompson, S. A.; Wafford, K. A. Neuronally
Restricted RNA Splicing Regulates the Expression of a Novel
GABAA Receptor Subunit Conferring Atypical Functional Properties.
J. Neurosci. 1997, 17, 5027-5037. (d) Bonnert, T. P.; McKernan,
R. M.; Farrar, S.; Le Bourdelles, B.; Heavens, R. P.; Smith, D. W.;
Hewson, L.; Rigby, M. R.; Sirinathsinghji, D. J. S.; Brown, N.;
Wafford, K. A.; Whiting, P. J. θ, A Novel γ-Aminobutyric Acid
Type A Receptor Subunit. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
9891-9896. (e) Barnard, E. A.; Skolnick, P.; Olsen, R. W.; Mohler,
H.; Sieghart, W.; Biggio, G.; Braestrup, C.; Bateson, A. N.; Langer,
S. Z. Subtypes of γ-aminobutyric acid A Receptors: Classification
on the Basis of Subunit Structure and Receptor Function. Int. Union
Pharmacol. XV. Pharmacol. ReV. 1998, 50, 291-313.
(5) McKernan, R. M.; Whiting, P. J. Which GABA-A Receptor Subtypes
Really Occur in the Brain? Trends Neurosci. 1996, 19, 139-143.
(6) Farrar, S. J.; Whiting, P. J.; Bonnert, T. P.; McKernan, R. M.
Stoichiometry of a Ligand-Gated Ion Channel Determined by
Fluorescence Energy Transfer. J. Biol. Chem. 1999, 274, 10100-
10104.
(7) Sieghart, W. Structure and Pharmacology of γ-Aminobutyric Acid-A
Receptor Subtypes. Pharmacol. ReV. 1995, 47, 181-234.
(8) Puia, G.; Vincini, S.; Seeburg, P. H.; Costa, E. Influence of
Recombinant γ-Aminobutyric acidA Receptor Subunit Composition
on the Action of Allosteric Modulators of γ-Aminobutyric Acid-
Gated Cl- Currents. Mol. Pharmacol. 1991, 39, 691-696.
(9) Rudolph, U.; Crestani, F.; Benke, D.; Brunig, I.; Benson, J. A.;
Fritschy, J. M.; Martin, J. R.; Bluethmann, H.; Mohler, H. Benzo-
diazepine Actions Mediated by Specific γ-Aminobutyric acid(A)
Receptor Subtypes. Nature 1999, 401, 796-800.
(10) McKernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur, C.; Wafford,
K. A.; Atack, J. R.; Farrar, S.; Myers, J.; Cook, G.; Ferris, P.; Garrett,
L.; Bristow, L.; Marshall, G.; Macaulay, A.; Brown, N.; Howell,
O.; Moore, K. W.; Carling, R. W.; Street, L. J.; Castro, J. L.; Ragan,
C. I.; Dawson, G. R.; Whiting, P. J. Sedative but not Anxiolytic
Properties of Benzodiazepines are Mediated by the GABAA Receptor
R1 subtype. Nat. Neurosci. 2000, 3, 587-592.
(11) Low, K.; Crestani, F.; Keist, R.; Benke, D.; Brunig, I.; Benson, J.
A.; Fritschy, J.-M.; Rulicke, T.; Bluethmann, H.; Mohler, H.;
Rudolph, U. Molecular and Neuronal Substrate for the Selective
Attenuation of Anxiety. Science 2000, 290, 131-134.
(26) Chambers, M. S.; Goodacre, S. C.; Hallett, D. J.; Jennings, A.; Jones,
P.; Lewis, R. T.; Moore, K. W.; Russell, M. G. N.; Street, L. J.;
Szekeres, H. J. Imidazopyrimidine Derivatives as Ligands for GABA
Receptors, and Their Preparation, Pharmaceutical Compositions, and
use in the Treatment of Adverse Neurological Conditions. World
Patent WO 02/074773, 2002.
(27) Chambers, M. S.; Goodacre, S. C.; Hallett, D. J.; Jennings, A.; Jones,
P.; Lewis, R. T.; Moore, K. W.; Russell, M. G. N.; Street, L. J.;
Szekeres, H. J. Imidazo-pyrimidine Derivatives as Ligands for GABA
Receptors, and their Preparation, Pharmaceutical Compositions, and
use in the Treatment of Adverse Neurological Conditions. World
Patent WO 02/074772, 2002.
(12) Collinson, N.; Kuenzi, F. M.; Jarolimek, W.; Maubach, K. A.;
Cothliff, R.; Sur, C.; Smith, A.; Out, F. M.; Howell, O.; Atack, J.
R.; McKernan, R. M.; Seabrook, G. R.; Dawson, G. R.; Whiting, P.
J.; Rosahl, T. W. Enhanced Learning and Memory and Altered
GABAergic Synaptic Transmission in Mice Lacking the R5 Subunit
of the GABAA Receptor. J. Neurosci. 2002, 22, 5572-5580.
(13) Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.; Isted, C.;
Leeson, P. D.; Thomas, S.; O’Connor, D.; McKernan, R. M.; Quirk,
K.; Cook, S. M.; Atack, J. R.; Wafford, K. A.; Thompson, S. A.;
Dawson, G. R.; Ferris, P.; Castro J. L. 3-Phenyl-6-(2-pyridyl)-
methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High
Affinity GABAA Benzodiazepine Receptor Ligands with R2, R3, and
R5-Subtype Binding Selectivity over R1. J. Med. Chem. 2004, 47,
1807-1822.
(14) Russell, M. G. N.; Carling, R. W.; Atack, J. R.; Bromidge, F.; Cook,
S. M.; Hunt, P.; Isted, C.; Lucas, M.; McKernan, R. M.; Mitchinson,
A.; Moore, K. W.; Narquizian, R.; Macaulay, A. J.; Thomas, D.;
Thompson, S. A.; Wafford, K. A.; Castro, J. L. Discovery of
Functionally Selective 7,8,9,10-Tetrahydro-7,10-ethano-1,2,4-triazolo-
[3,4-a]phthalazines as GABAA Receptor Agonists at the R3 Subunit.
J. Med. Chem. 2005, 48, 1367-1383.
(15) Atack, J. R. The Benzodiazepine Binding Site of GABAA Receptors
as a Target for the Development of Novel Anxiolytics. Expert Opin.
InVest. Drugs 2005, 14 (5), 601-618.
(28) Jensen, M. S.; Hoerrner, R. S.; Li, W.; Nelson, D. P.; Javadi, G. J.;
Dormer, P. G.; Cai, D.; Larsen, R. D. Efficient Synthesis of a
GABAA R2,3-Selective Allosteric Modulator via a Sequential Pd-
Catalyzed Cross-Coupling Approach. J. Org. Chem. 2005, 70 (15),
6034-6039.
(29) Li, W.; Cai, D.; Hoerrner, R. S.; Jensen, M. S.; Larsen, R. D.; Petasis,
N. A. Preparation of Substituted Imidazopyrimidines. World Patent
WO 03/080621, 2003.
(30) Atack, J. R.; Smith, A. J.; Emms, F.; McKernan, R. M. Regional
Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788
Binding Reflect Selectivity for R1 versus R3 Subunit-Containing
GABAA Receptors. Neuropsychopharmacology 1999, 20, 255-262.
(31) Dawson, G. R.; Tricklebank, M. D. Use of the Elevated Plus Maze
in the Search of Novel Anxiolytic Agents. Trends Pharm. Sci. 1995,
16, 33-36.
(32) Bayley, P.; Bentley, G. D.; Jackson, A.; Williamson, D.; Dawson,
G. R. Comparison of Benzodiazepine (BZ) Receptor Agonists in Two
Rodent Activity Tests. J. Psychopharmacol. 1996, 10, 206-213.
(33) A preliminary account of this work was recently presented. Street,
L. J. 229th Meeting of the American Chemical Society, San Diego,
March 2005; American Chemical Society: Washington, DC, 2005;
MEDI 022.
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