7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy) -3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: A functionally selective γ-aminobutyric acidA (GABAA) α2/α3- subtype selective agonist that exhibits potent anxiolyti

Article abstract of DOI:10.1021/jm058034a

There is increasing evidence that compounds with selectivity for γ-aminobutyric acid_A (GABA_A) α2- and/or α3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect pro

Full text of DOI:10.1021/jm058034a

© Copyright 2005 by the American Chemical Society
Volume 48, Number 23
November 17, 2005
Letters
(R1-R6, â1-â3, γ1-γ3, δ, ꢀ, π, and θ).3 Expression of
7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-
triazol-3-ylmethoxy)-3-(2-fluorophenyl)-
1,2,4-triazolo[4,3-b]pyridazine: A
Functionally Selective γ-Aminobutyric
AcidA (GABAA) r2/r3-Subtype Selective
Agonist That Exhibits Potent Anxiolytic
Activity but Is Not Sedating in Animal
Models
recombinant 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 chan-
nel,3,4 with recent studies suggesting a subunit stoichi-
ometry of two R, two â, and one γ subunit.5 As well as
an agonist (GABA) binding site, GABAA receptors also
have multiple allosteric modulatory sites for barbitu-
rates, neurosteroids, anesthetics, avermectins, and ben-
zodiazepines that all modulate opening of the channel.6
Of these, the benzodiazepine site is the best character-
ized because of its role in mediating the clinical effects
of anxiolytics such as diazepam (1). It has been shown
that the major benzodiazepine sensitive GABAA receptor
subtypes in brain are R1âγ2, R2âγ2, R3âγ2, and R5âγ2.4
Currently used anxiolytic benzodiazepines such as di-
azepam (1) are nonselective, high-efficacy agonists, and
these compounds show sedative,7 muscle-relaxant,8 and
amnesic9 properties. Zolpidem (2), which has higher
affinity for R1- (the major subtype of GABAA receptors
in the central nervous system)4 over R2-, R3-, and R5-
containing receptors, is particularly sedative in animal
tests and in man.10 This suggests that compounds with
Robert W. Carling,* Andrew Madin, Alec Guiblin,
Michael G. N. Russell, Kevin W. Moore,
Andrew Mitchinson, Bindi Sohal, Andrew Pike,
Susan M. Cook, Ian C. Ragan, Ruth M. McKernan,
Kathleen Quirk, Pushpinder Ferris, George Marshall,
Sally Ann Thompson, Keith A. Wafford,
Gerard R. Dawson, John R. Atack, Timothy Harrison,
Jose´ L. Castro,* and Leslie J. Street*
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.
Received June 16, 2005
Abstract: There is increasing evidence that compounds with
selectivity for γ-aminobutyric acidA (GABAA) R2- and/or R3-
subtypes may retain the desirable anxiolytic activity of
nonselective benzodiazepines but possess an improved side
effect profile. Herein we describe a novel series of GABAA R2/
R3 subtype-selective agonists leading to the identification of
the development candidate 17, a nonsedating anxiolytic in
preclinical animal assays.
reduced affinity and/or efficacy at R1-containing GABAA
receptors, yet with affinity and efficacy at R2- and/or
R3-subtypes, may retain the desirable anxiolytic activity
of nonselective benzodiazepines and possess an im-
proved side effect profile (i.e., reduced sedation). Further
evidence for the role of R1-containing receptors in
sedation has been provided by the use of transgenic mice
in which the R1 subunit was rendered benzodiazepine-
insensitive.11,12 In these animals, the anxiolytic, anti-
convulsant, and myorelaxant effects of diazepam were
preserved, while its sedative and amnesic effects were
significantly reduced. To date, only a limited number
GABA (γ-aminobutyric acid) is the major inhibitory
neurotransmitter in the brain,1 and GABAA receptors
constitute the largest population of inhibitory neu-
rotransmitter receptors.2 The purification, sequencing,
and cloning of the GABAA receptor have led to the
identification of 16 subunits arranged within 7 families
* To whom correspondence should be addressed. For R. C.: phone,
(+1279) 440000; fax, (+1279) 440187; e-mail, robert_carling@merck.com.
For J.L.C.: phone, (+1279) 440000; fax, (+1279) 440187; e-mail,
jose_castro_pineiro@merck.com. For L.J.S.: phone, (+1279) 440000;
fax, (+1279) 440187; e-mail, leslie_street@merck.com.
10.1021/jm058034a CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/14/2005

7090 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Letters
Scheme 1a
Table 1. Affinities and Efficacies of Triazolopyridazines at
Cloned Human GABAA Receptorsf
a Reagents: (i) ArCONHNH2, xylene or 1,4-dioxan, Et3N.HCl,
reflux; (ii) HetCH2OH, NaH, DMF; (iii) RCO2H, (NH4)2S2O8,
AgNO3, H2SO4, H2O, 70 °C; (iv) NH2NH2‚H2O, AcOH, NaOAc,
reflux; (v) POCl3, (vi) NH2NH2‚H2O, EtOH reflux; (vii) ArCOCl,
pyridine; (viii) dioxan, HCl, reflux.
key compounds, efficacies were determined using whole-
cell patch clamp recordings from L(tk-) cells stably
expressing R1â3γ2, R2â3γ2, or R3â3γ2 GABAA receptor
subtypes using increasing concentrations of test ligand
to measure the concentration response.14,20
Replacement of the 2-pyridyl ring of the triazolopy-
ridazine 3 with 1,2,4-triazoles linked through the 3-po-
sition led to the identification of GABAA ligands that
had higher efficacy at R3- than R1-containing recep-
tors.21 Removal of the [2.2.2] bicyclic ring of compound
3 and substitution of the 7-position of the triazolopy-
ridazine core with phenyl led to a nonselective high
affinity/high efficacy agonist 11 (Table 1). Combining
these changes led to the 3,7-diphenyl derivative 12,
which not only has high affinity at R1-, R2-, and R3-
containing GABAA receptors but also has marginal
functional selectivity favoring R3 (+115%) over R1
(+94%) receptors. Replacing 7-phenyl with 7-cyclohexyl
to give 13 resulted in a comparable efficacy profile but
somewhat reduced affinity. To lower efficacy at R1-
containing receptors (ideally silent antagonist), the
effect of reducing the size of the 7-substituent, therefore
local hydrophobicity, was investigated.17,22,23 These
changes were carried out using the chemistry outlined
in Scheme 1.24 Thus 3,6-dichloropyridazine 4 could be
transformed in two steps to a generic triazolopyridazine
(6) and then converted to the general structure 7 by
radical addition. Alternatively, 4 could be subjected to
radical attack first to give 8, which could then be
converted in two steps to the target 7. In the case of
7-phenyl, this substituent was introduced starting from
phenylmaleic anhydride, which in five steps was trans-
formed to 8. Replacing phenyl 12 with cyclopentyl to
give 14 not only reduced R1 efficacy and retained
functional selectivity but also had the added benefit of
increasing R3 affinity. The 7-cyclobutyl derivative 15
showed a further reduction in R1 efficacy but retained
higher efficacy at R3 and high affinity. Introduction of
a tert-butyl group at the 7-position to give 16 resulted
in a high-affinity GABAA ligand that was an antagonist
at R1-containing receptors and still had positive modu-
lation at R3 receptors. However, 16 was not considered
a All compounds were characterized by proton NMR and mass
spectra and gave satisfactory elemental analysis results. b Dis-
placement of [3H]Ro 15-1788 from human recombinant GABAA
receptors Rxâ3γ2 (x ) 1, 2, or 3). Ki values are the mean of at
least two independent determinations (where n ) 2; individual
data given).. c Efficacy is determined as the percent modulation
of the submaximal (EC20) response to GABA in human GABAA
receptor expressed transiently in Xenopus laevis oocytes. d Efficacy
is determined as the percent modulation of the submaximal (EC20
)
response to GABA in human GABAA receptor expressed stably in
L(tk-) cells. e n/d: not determined. f It is noted that as this
particular series of compounds was developed, we refined our
screening strategy from one in which we measured efficacy of a
single drug concentration at R1, R2 and R3 subtypes transiently
expressed in Xenopus oocytes to one in which multiple drug
concentrations were assessed in stably transfected fibroblasts, the
latter of which increased our precision but reduced our throughput
(hence, R2 data were not available for all compounds).
of GABAA R2/R3-subtype selective ligands have been
reported in the literature.12-16 We disclosed 3 as a
GABAA R2/R3 agonist that had moderately higher
affinity at R2- and R3- compared to R1-containing
receptors.17 In this communication we describe optimi-
zation studies carried out on 3 that ultimately led to
the identification of the development candidate 17, a
GABAA R1 antagonist and an R2/R3 agonist that has
anxiolytic activity in animal models and is not sedating.
Compounds were tested for their ability to inhibit the
binding of [3H]Ro15-1788 to the benzodiazepine binding
site of different R-subunit-containing (â3, γ2, plus an
R1, R2, or R3) human recombinant GABAA receptors
stably expressed in L(tk-) cells.18 Efficacies of most
compounds were determined at GABAA receptors con-
taining these same subunit combinations transiently
expressed in Xenopus oocytes by measurement of the
modulatory effect on the GABA EC20 ion current using
two-electrode voltage-clamp electrophysiology at a single
maximal concentration of test ligand (100 × Ki).19 For

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7091
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Figure 1. Efficacy of 17 expressed relative to a nonselective
full agonist in the rat elevated plus maze (anxiolytic) and
chain-pulling (sedation) assays. In the elevated plus maze, the
percent time spent on the open arms during the 5 min trial
time is expressed relative to the increase seen with the
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chain-pulling assay, the decrease in the mean rate of respond-
ing over the 60 min trial period was compared to diazepam
(10 mg/kg). The clear separation between anxiolysis and
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Bromidge, F.; Quirk, K.; Atack, J. R.; McKernan, R. M.;
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to be a development candidate because metabolism
studies showed that triazolopyridazines with an unsub-
stituted 3-phenyl ring have a tendency to undergo
extensive glutathione incorporation in vivo. In an at-
tempt to overcome this problem, fluorination of the
phenyl ring was explored leading to the identification
of the development candidate 7-(1,1-dimethylethyl)-6-
(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-
1,2,4-triazolo[4,3-b]pyridazine (17, TPA023). Compound
17 is a high-affinity antagonist at R1-containing recep-
tors but is a high-affinity, low-efficacy partial agonist
at R2 and R3 receptors; it has good pharmacokinetics
in rat and dog (rat, F ) 35%, t1/2 ) 1.4 h; dog, F ) 53%,
t1/2 ) 1.5 h) and has excellent occupancy of central
GABAA receptors following oral dosing ([3H]Ro15-1788)
binding assay25 ID50 ) 0.42 mg/kg, Tmax ) 0.5 h). The
pharmacokinetic properties of 17 and lack of efficacy
at the R5 subtype (modulation of a GABA EC20 ) 6%)
confer advantages over L-838417,26 whereas 17 lacks
both R1 and R5 efficacy relative to 15 (TP1327). When
tested in the standard rat anxiety assay, the elevated
plus maze assay (Figure 1),28 17 was anxiolytic at doses
of 1 and 3 mg/kg po (corresponding to 70% and 88%
occupancy, respectively) without causing significant
impairment at a dose of 30 mg/kg po (99% occupancy)
in the rat chain-pulling and mouse rotarod assays of
myorelaxation and/or ataxia.29 Compound 17 was also
a nonsedating anxiolytic in primates29 and in baboons
did not cause self-administration nor did it produce
subjective feelings similar to the nonselective full ago-
nist lorazepam.30 These data clearly suggest that 17
possesses a preclinical profile unlike existing nonselec-
tive benzodiazepines and suggest that anxiolytic efficacy
can be separated from sedation and dependence.30
Supporting Information Available: Experimental pro-
cedures for synthesis and characterization of intermediates
and final products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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