Selective, Orally Active γ-Aminobutyric AcidA α5 Receptor Inverse Agonists as Cognition Enhancers

Article abstract of DOI:10.1021/jm031076j

Nonselective inverse agonists at the γ-aminobutyric acid_A (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A α5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.

Full text of DOI:10.1021/jm031076j

2
176
J . Med. Chem. 2004, 47, 2176-2179
Selective, Or a lly Active γ-Am in obu tyr ic
Acid A r5 Recep tor In ver se Agon ists a s
Cogn ition En h a n cer s
gional variations. For example, the R5-subunit-contain-
ing receptors represent less than 5% of total brain
GABA-A receptors, yet in the hippocampus, a region of
the brain associated with learning and memory pro-
cesses, they constitute 20% of all GABA-A receptors.2
Nonselective BZ agonists (similar activity at the
different GABA-A receptor subtypes) such as diazepam
,3
Francine Sternfeld,* Robert W. Carling,
Richard A. J elley, Tamara Ladduwahetty,
Kevin J . Merchant, Kevin W. Moore, Austin J . Reeve,
Leslie J . Street, Desmond O’Connor, Bindi Sohal,
J ohn R. Atack, Susan Cook, Guy Seabrook,
Keith Wafford, F. David Tattersall, Neil Collinson,
Gerard R. Dawson, J os e´ L. Castro, and
Angus M. MacLeod
(
1) are used clinically for the treatment of anxiety and
4
epilepsy. However, they also induce amnesia in humans
The Neuroscience Research Centre,
Merck Sharp and Dohme Research Laboratories,
Terlings Park, Eastwick Road,
Harlow, Essex, CM20 2QR, U.K.
Received October 24, 2003
and animals.5,6 Conversely, nonselective BZ receptor
inverse agonists have cognition-enhancing effects in
Abstr a ct: Nonselective inverse agonists at the γ-aminobutyric
acid (GABA-A) benzodiazepine binding site have cognition-
A
7
8
9
enhancing effects in animals but are anxiogenic and can
precipitate convulsions. Herein, we describe novel GABA-A R5
subtype inverse agonists leading to the identification of 16 as
an orally active, functionally selective compound that enhances
cognition in animals without anxiogenic or convulsant effects.
Compounds of this type may be useful in the symptomatic
treatment of memory impairment associated with Alzheimer’s
disease and related dementias.
animal models but are anxiogenic and convulsant or
10
proconvulsant and, as such, cannot be used to treat
cognitive deficits in humans. By use of genetically
modified (knock-in) mice, it has been demonstrated that
R1-subunit-containing GABA-A receptors mediate seda-
tive/muscle-relaxant effects while R2/R3-subunit-con-
taining receptors mediate anxiolytic and anticonvulsant
1
1-13
effects.
The role of R5-subunit-containing receptors,
γ-Aminobutyric acid (GABA) is the major inhibitory
neurotransmitter in mammalian brain, and γ-aminobu-
tyric acidA (GABA-A) receptors constitute the largest
population of inhibitory neurotransmitter receptors. The
GABA-A receptor is a GABA-gated chloride ion channel
with multiple allosteric modulatory sites, in addition to
the GABA binding site, and the benzodiazepine (BZ) site
is one of the most studied of these. Ligands that bind
to the BZ site can influence the binding of GABA to the
receptor and thereby alter the flux of chloride ions
through the ion channel. Ligands at the BZ site are
categorized as agonists, inverse agonists, or antagonists.
Agonists act by increasing the frequency of channel
opening to give a net hyperpolarization of the neuron
and a decreased excitability. BZ inverse agonists have
the opposite effect and decrease the frequency of channel
openings, resulting in a depolarization and an increased
neuronal excitability. Between the two efficacy ex-
tremes, there is a continuum of partial agonists and
partial inverse agonists as well as antagonists that do
not alter chloride flow and are functionally silent. These
different efficacies are reflected in different behavioral
effects of BZ site ligands.
however, remains largely undefined. Given the abun-
dance of R5-subunit-containing receptors in the hippoc-
14
ampus, it has been hypothesized that this subtype may
15
be involved in cognitive processes. Further, we have
proposed that a selective R5 inverse agonist may have
therapeutic utility as a cognition-enhancing agent with-
out the unwanted side effects associated with activity
at other receptor subtypes. Most drugs currently used
in the treatment of cognitive deficiency act through the
cholinergic system and have moderate clinical efficacy.
GABA-A R5 subtype selective inverse agonists may offer
an alternative mechanism for the symptomatic treat-
ment of memory impairment associated with Alzhe-
imer’s disease and related dementias.
Of the numerous structural classes that have been
shown to bind to the BZ site, relatively few are selective
for the R5 subtype. These include imidazobenzodiaz-
16
epines (e.g., FG 8094, 2) and some diazepam ana-
17
logues, both of which exhibit binding selectivity for R5-
subunit-containing receptors compared to the other
receptor subtypes. In addition, we recently described
novel 6,7-dihydro-2-benzothiophen-4(5H)-ones (e.g., 3)
18,19
that have binding selectivity for the R5 subtype.
GABA-A receptors are pentameric assemblies of a
large range of subunits (R1-6, â1-3, γ1-3, δ, ꢀ, π, and
θ), of which the R subunit is of particular importance
in determining the pharmacology of the BZ binding
However, typically these compounds had low oral bio-
availability in animals, preventing their further devel-
opment. In this communication, we describe the design,
synthesis, and biological evaluation of orally active
GABA-A R5 receptor inverse agonists leading to the
identification of an efficacy selective compound that
enhances cognition in animals while being devoid of
anxiogenic, convulsant, and proconvulsant activity.
In this study, the efficacies of compounds at the
GABA-A receptor subtypes were determined at cloned
1
site. The major BZ-sensitive GABA-A receptor subtypes
in the brain are R1âxγ2, R2âxγ2, R3âxγ2, and R5âxγ2,
and their distribution in the brain shows distinct re-
*
To whom correspondence should be addressed. Phone: (01144)
279-440412. Fax: (01144) 1279-440390. E-mail: francine_sternfeld@
merck.com.
1
1
0.1021/jm031076j CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9 2177
Ta ble 1. Binding Affinities and Efficacies of Bicyclo-2.2.2-Triazolopyridazines at Cloned Human GABA-A Receptor Subtypes
a
3
Displacement of [ H]Ro 15-1788 binding from recombinant human GABA-A receptor subtypes. Ki values are the mean of at least two
independent determinations; the standard error of the mean (SEM) is given where at least three independent determinations were
b
performed. Efficacy is determined as the percentage modulation of the submaximal (EC20) response to GABA. Values are the arthimetic
mean ( SEM of at least three independent cells from GABA-A receptor subtypes transiently expressed in Xenopus laevis oocytes.
human R1-, R2-, R3-, and R5-containing receptors tran-
siently expressed in Xenopus oocytes by measurement
of the modulatory effect on the GABA EC20 ion current
Sch em e 1a
2
0
using two-electrode voltage clamp electrophysiology.
The efficacy scale from full inverse agonist to full agonist
is unsymmetrically distributed about the point of zero
efficacy (antagonism). Thus, methyl 6,7-dimethoxy-4-
ethyl-â-carboline-3-carboxylate (DMCM), which is re-
garded as a nonselective full inverse agonist, has an
efficacy of -52% at R5-containing receptors while that
of the nonselective full agonist chlordiazepoxide (CDZ)
is +134%; a similar pattern is observed at the other
receptor subtypes (Table 1).
The starting point for our work was the triazolopy-
ridazine 4 prepared in the course of the Merck GABA-A
R2/R3 agonist program for the discovery of novel anxi-
olytics.21 4 has high GABA-A R5 receptor affinity
combined with 8- to 40-fold binding selectivity over
GABA-A R1, R2, and R3 receptor subtypes (Table 1); it
is, however, a very low-efficacy partial agonist at
GABA-A R5 receptors with somewhat higher efficacies
at the other receptor subtypes. Other groups have
demonstrated that the conversion of GABA-A receptor
inverse agonists and antagonists to partial agonists can
be achieved within structural classes by the introduction
of appropriate lipophilicity.22,23 On the basis of this
precedent, the C-3 phenyl substituent of 4 was replaced
with the more hydrophilic oxadiazole ring to give 5. This
resulted in a dramatic switch in the R5 efficacy profile
to give an inverse agonist (-35%) while maintaining
excellent R5 affinity (Table 1). 5 displays somewhat
weaker inverse agonism at R1, R2, and R3 receptors. A
range of different C-3 heterocycles was investigated
using the chemistry shown in Scheme 1.24 Thus, conver-
sion of the 3,6-dichloropyridazines 6 to the monohy-
a Reagents: (i) NH NH ‚H O, EtOH, reflux; (ii) (a) RCO H, CDI,
DMF or RCO2H, BOPCl, Et3N, CH2Cl2; (b) cat. Et3N‚HCl, xylene,
reflux; (iii) RCOCl, Et3N, room temp, then reflux; (iv) HetCH2OH,
NaH or LHMDS, DMF.
2
2
2
2
drazinopyridazines 7 followed by coupling with hetero-
cyclic carboxylic acids and dehydration gave the 6-chloro-
pyridazines 8. Reaction of 8 with alkoxides gave deriva-
tives with the general structure 9. The results shown
in Table 1 demonstrate that a range of different
heterocycles was tolerated at the C-3 position, the
compounds displaying high R5 affinity and a range of
efficacies with the level of inverse agonism being de-
pendent on the hydrophilicity of the heterocycle (e.g.,
10 and 11). All analogues showed higher affinity at R5
receptors than at the other subtypes, particularly

2
178 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9
Letters
Ta ble 2. Binding Affinities and Efficacies of Triazolophthalazines at Cloned Human GABA-A Receptor Subtypes
a
3
Displacement of [ H]Ro 15-1788 binding from recombinant human GABA-A receptor subtypes. Ki values are the mean of at least two
independent determinations; the standard error of the mean (SEM) is given where at least three independent determinations were
b
performed. Efficacy is determined as the percentage modulation of the submaximal (EC20) response to GABA. Values are the arthimetic
mean ( SEM of at least three independent cells from GABA-A receptor subtypes transiently expressed in Xenopus laevis oocytes.
compared to R1-containing receptors (40- to 75-fold). As
well as displaying excellent binding selectivity, the
furan 11 and isoxazole 12 also showed functional
selectivity for the R5 subtype, being inverse agonists at
R5 and weak partial agonists or antagonists at R1, R2,
and R3. Unfortunately, neither of these compounds were
orally bioavailable in rats. In particular, both com-
pounds were found to be rapidly and extensively me-
tabolized when incubated with rat liver microsomes, and
a detailed study revealed that a major route of metabo-
lism, in vitro and in vivo, for compounds of this class
was through hydroxylation of the [2.2.2]-bicyclic ring
system. To remove this source of metabolism, the
bicyclic ring system was modified to afford triazoloph-
thalazines (Scheme 1, Table 2).
functional selectivity (Table 2). The position of the
methyl substituent on the triazole ring proved critical,
giving rise to subtle changes in the overall efficacy
profile of the isomers that manifested itself in vivo.
Thus, 15 and 17 were proconvulsant in the PTZ assay
while 16 showed no effects at doses that occupied
approximately 95% of R5 receptors. 16 also showed no
2
7
anxiogenic effects in rats at doses that gave greater
2
8
than 85% occupancy of BZ receptors and was orally
bioavailable in rats, dogs, and rhesus monkeys. In the
delayed matching to position test in the water maze,29
a hippocampal-dependent cognitive assay, 16 signifi-
cantly enhanced the performance of rats at an oral dose
of 0.3 mg/kg, corresponding to approximately 40% of BZ
receptor sites being occupied. Thus, 16 enhances cogni-
tion in animals without anxiolytic, convulsant, or pro-
convulsant side effects and, on the basis of its overall
in vitro and in vivo profile, was selected for clinical
evaluation.
1
3, the triazolophthalazine analogue of 12, retained
excellent R5 binding affinity and functional selectivity,
although there was a modest reduction in the level of
R5 inverse agonism. Interestingly, replacement of the
[2.2.2] bicycle led to complete loss of R5 binding selectiv-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of 16 and NMR and mass spectral data,
microanalysis results, and melting points for test compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ity. Although 13 showed poor oral bioavailability in rats,
deletion of the methyl group from the C-6 pyridyl
substituent (14) yielded good bioavailability (41%). 14
has subnanomolar R5 affinity and, although it has no
binding selectivity, shows enhanced functional selectiv-
ity compared to 12. Although 14 was not convulsant
when dosed alone to mice, it was proconvulsant, poten-
tiating pentylenetetrazole (PTZ) induced seizures in
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J M031076J