Identification of an orally bioavailable, potent, and selective inhibitor of GlyT1

Article abstract of DOI:10.1021/ml1001085

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus mon

Full text of DOI:10.1021/ml1001085

pubs.acs.org/acsmedchemlett
Identification of an Orally Bioavailable, Potent, and
Selective Inhibitor of GlyT1
Wesley P. Blackaby,*,†,§ Richard T. Lewis,† Joanne L. Thomson,† Andrew S. R. Jennings,†
Simon C. Goodacre,† Leslie J. Street,† Angus M. MacLeod,† Andrew Pike,† Suzanne Wood,†
Steve Thomas,† Terry A. Brown,† Alison Smith,† Gopalan Pillai,† Sarah Almond,†
Martin R. Guscott,† H. Donald Burns,‡ Waisi Eng,‡ Christine Ryan,‡ Jacquelynn Cook,‡ and
Terence G. Hamill‡
†Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR,
United Kingdom, and ‡Research Imaging, Merck Research Laboratories, West Point, Pennsylvania 19486
ABSTRACT Amalgamation of the structure-activity relationship of two series of
GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate,
compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of
GlyT1 transporters in rhesus monkey as determined by displacement of a PET
tracer ligand.
KEYWORDS Inhibitor, GlyT1, structure-activity relationship, DCCCyB, PET tracer
ligand
he hypofunction of N-methyl-D-aspartate (NMDA) re-
ceptors has been implicated in the pathophysiology of
schizophrenia, with evidence coming from both pre-
However, compound 1 was shown to have unacceptably
high covalent binding in vivo to both rat liver and plasma
proteins after oral dosing at 20 mg/kg (6 h postdose: liver,
153 pmol equiv/mg protein; plasma, 214 pmol equiv/mg
protein). Metabolite identification experiments using radio-
labeled piperidine sulfonamide analogues, or trapping ex-
periments with radiolabeled cyanide, led us to hypothesize
that the observed covalent binding was due to oxidation of
the piperidine ring leading to the formation of a reactive
species. High levels of covalent binding have been linked
to increased incidence of idiosyncratic toxicities of com-
pounds in the clinic;18 therefore, further chemical optimiza-
tion was undertaken in the sulfone series. The required
cyclohexyl sulfone derivatives were accessed as delineated
in Scheme 1.19 The cis and trans isomers of the key alcohol
intermediate A were separated chromatographically and
assigned based upon nuclear Overhauser effect NMR experi-
ments.
Where the required thiol was readily available, formation
of the mesylate of A followed by displacement gave the
thioether. Alternatively, the thioether was accessed via
Mitsunobu chemistry with thioacetate followed by a one-
pot deprotection-alkylation protocol. Oxidation of the
thioether with oxone gave the required final compound.
The inhibition at hGlyT1 transporters and microsomal
turnover in rat and human microsomes for a selection
of heterocyclic sulfone compounds is given in Table 1.
T
clinical models1-3 and the limited clinical data available.4-10
The latter includes the reversible psychosis induced in non-
schizophrenics by NMDA antagonists such as phencyclidine
(PCP), and the clinical efficacy observed when antipsychotic
medication was supplemented with the obligatory NMDA
coagonist glycine or with sarcosine, a weak endogenous
inhibitor of type 1 glycine uptake transporters (GlyT1). Most
importantly, this adjunctive therapy has been shown to give
significant improvements in the negative and cognitive
symptoms of stable schizophrenics, for which significant
unmet medical need remains due to the lack of efficacy of
conventional antipsychotics against these symptoms.6 In
the brain, glycine levels are thought to be maintained
tonically at submaximal concentrations in the synapse by
GlyT1.11 This suggests that the pharmacological manipula-
tion of synaptic glycine concentration using a GlyT1 inhibitor
may be a viable method of potentiating NMDA receptor
function in vivo, hence ameliorating the negative and cog-
nitive symptoms of schizophrenia. To test this hypothesis,
there has been an industry wide effort to identify potent and
selective GlyT1 inhibitors.12-15
Recent communications from our laboratory have dis-
closed two related series of hGlyT1 inhibitors, typified by the
piperidine sulfonamide 116 and cyclohexyl sulfone 2,17
which demonstrate excellent selectivity over the related
GlyT2 and TauT transporters (Figure 1). Early issues for the
piperidine series were poor oral bioavailability in rat and dog
due to high plasma clearance, although this was resolved in
the 2,4-dichlorophenyl analogue 1.
Received Date: May 11, 2010
Accepted Date: June 21, 2010
Published on Web Date: June 25, 2010
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Table 1. hGlyT1 Potency and Human and Rat Liver Microsomal
Turnover of Selected Heterocyclic Sulfone Analogues
Figure 1. Structures of hGlyT1 inhibitors.
Scheme 1a
a IC50 values are averages of at least two measurements. The hGlyT1a
isoform was used for the assay. b Turnoverof GlyT1 compounds (1 μM) in
rat and human liver microsomes. All incubations were carried out at
37 °C for 15 min. Protein concentration = 0.5 mg/mL; cosolvent =
0.99% MeCN þ 0.01% DMSO. For compounds in this series, LM %
turnover e40 was considered acceptable for further compound pro-
gression.
a Reagents and conditions: (a) KHMDS, THF and then cyclopropyl-
methyl bromide. (b) LiAlH4, Et2O. (c) 2,4-Dichlorobenzoyl chloride,
Hunigs base, DCM. (d) HCl(aq), THF. (e) NaBH4, EtOH. (f) Chromato-
graphic separation of isomers. (g) MsCl, pyr and then RSNa. (h) PPh3,
N2(CO2iPr)2, thioacetate. (i) LiOH, THF/H2O and then RBr. (j) Oxone,
acetone/water.
Compound 2 exhibited excellent oral bioavailability in
the rat and occupied GlyT1 transporters in vivo, as adjudged
by our previously reported in vivo binding assay in the
rat20 using a proprietary GlyT1 radiolabel, with an Occ50 of
3.4 mg/kg.17 Analysis of the plasma and brain drug levels
required to achieve Occ50 (1.2 and 0.2 μM, respectively)
revealed a low brain to plasma ratio of 0.16. A similarly low
brain to plasma ratio of 0.1 was determined from a 10 mg/kg
oral dose of compound 3. A subsequent study in mdrla þ/þ
and -/- mice determined the ratio between the brain:blood
ratios of the -/- and þ/þ animals to be 8.7, suggesting
compound 3 to be a P-gp substrate.
Compound 2 did not inhibit common Cyp isoforms (2D6,
2C9, and 3A4: IC50 > 10 μM); however, the NH-triazole ana-
logues 4 and 5, potential metabolites of compounds 2 and 3,
respectively, proved to be extremely potent inhibitors of Cyp
2C9 (compound 5 Cyp 2C9: IC50 = 10 nM). The potent Cyp
inhibition, in combination with the high plasma Occ50 due to
the P-gp issue, precluded the further development of triazole
analogues 2 and 3. Heterocyclic sulfone analogues in which
the pendant alkyl group was linked through carbon exhibited
either increased microsomal turnover (6 and 7) or reduced
potency at hGlyT1 (8 and 9).
Investigation of simple alkyl sulfone derivatives related
to compound 1 (Table 2) established that the structure-
activity relationship (SAR) was reminiscent of the previously
described 4-pyridyl piperidine series16 with a significant
reduction in potency observed in the series propyl 10, ethyl
11, and methyl 12. In the alkyl sulfone series, a more
stringent requirement for the cis relationship between the
sulfone and the amide was observed than in the heterocyclic
series, with compounds 10 and 11 demonstrating >10-fold
greater potency relative to 13 and 14. Although the cyclo-
butylmethyl compound 15 demonstrated a loss in potency
relative to propyl analogue 10, the cyclopropylmethyl com-
pound 16 (DCCCyB) retained potency but with improved
microsomal stability. Compound 16 demonstrated an ac-
ceptable level of in vivo covalent binding (<25 pmol equiv/
mg after a 20 mg/kg oral dose) in the rat and was selected for
further profiling.
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Table 2. hGlyT1 Potency and Human and Rat Liver Microsomal
Turnover of Selected Alkyl Sulfone Analogues
Figure 2. Trials to criterion for ED shift. Asterisk-marked columns
denote significance at p < 0.05 vs PCP and vehicle for ED shift.
using proof of concept compounds, by in vivo dialysis
through a probe inserted into the rat frontal cortex. Glycine
levels were determined up to 4 h postdose with com-
pound 16 at 20 and 3 mg/kg po. Both doses significantly
elevated extracellular glycine levels above basal concentra-
tions (mean % peak glycine efflux as a % basal ( SEM;
20 mg/kg = 184.0 ( 17.0%; 3 mg/kg = 151.0 ( 25.0%).
The increase in glycine levels at the 3 mg/kg po dose of
compound 16 is consistent with that observed for other
GlyT1 inhibitors shown to be efficacious in animal models
of schizophrenia.21
a IC50 values are averages of at least two measurements. The hGlyT1a
isoform wasused for the assay. b Turnoverof GlyT1 compounds (1 μM) in
rat and human liver microsomes. All incubations were carried out at
37 °C for 15 min. Protein concentration = 0.5 mg/mL; cosolvent =
0.99% MeCN þ 0.01% DMSO. For compounds in this series, LM %
turnover e40 was considered acceptable for further compound pro-
gression.
Impairments in executive function have long been con-
sidered to be a core feature of schizophrenic illness,22 with
the attentional set shifting aspect of executive function
commonly assessed in patients using the Wisconsin Card
Sorting Test.23 The intra/extra dimensional (ED/ID) rodent
model of executive function can be used, following impair-
ment in perceptual attentional set shifting by PCP adminis-
tration, as a model for the set shifting deficits observed
in schizophrenic patients.24 In the rat ED/ID assay,25 com-
pound 16 dosed at 3 mg/kg po reversed the PCP-induced
cognitive deficit in the ED shift (Figure 2). Although all
discriminations were performed, for clarity, only the ED data
are shown as subchronic dosing of PCP induced a deficit
exclusively in this aspect of the assay.
Table 3. Pharmacokinetic Parameters of Compound 16 in Pre-
clinical Species
rat
rhesus
dog
dose (iv and po)
mg/kg
1.0
1.0
24
1.0
4.9
3.1
Cl
mL/min/kg
36
Vd(ss)
T1/2
F
L/kg
h
4.1
2.4
2.3
1.5
2
10
48
1.39
1.0
%
65
Cmax
Tmax
μM
h
0.14
0.8
0.04
2.7
The pharmacokinetic parameters of compound 16 in
preclinical species are given in Table 3. Clearance is low in
dogs and moderate in rats and rhesus monkey, and this
combined with moderate Vd(ss) in all species gave accep-
table half-life values. Oral bioavailability of 65 and 48% in rat
and dog, respectively, was obtained using the 0.5% metho-
cel suspension dosing vehicle.
Compound 16 was not a substrate for human or mouse
P-gp, had a significantly increased brain to plasma ratio of
2.3, and exhibited a lower plasma Occ50 of 0.35 μM in the rat
GlyT1 in vivo binding assay as compared to compound 2. No
significant off-target activity was observed for compound 16
in a broad ancillary pharmacology panel screen.
The availability of the GlyT1 PET tracer [18F]MK-657726
facilitated the evaluation of the plasma occupancy relation-
ship for compound 16 in higher species. Figure 3 shows the
time-activity curves and PET/MRI coregistered images from
the PET scans.27 The differences in tracer uptake under
baseline and blockade conditions can be used to determine
GlyT1 occupancy at different doses/plasma concentrations.
A plasma occupancy curve for 16 was generated giving rise
to an estimated plasma Occ50 concentration of 120 nM in
rhesus monkey, which is in good agreement with the plasma
Occ50 concentration generated in rat.
In summary, replacement of the piperidine ring of com-
pound 1 generated a series of cyclohexyl sulfone inhibitorsof
hGlyT1 and removed the in vivo covalent binding observed
with the former series. Reoptimization of the sulfone moiety
A GlyT1 inhibitor would be expected to lead to an
increase in the levels of extracellular glycine in the brain.
This has been demonstrated in the literature, and at Merck1
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Figure 3. (A)Time-activity curves for baseline ([18F]MK-6577 treated; filled markers) and for blockade ([18F]MK-6577 and cpd 16 treated;
no markers) conditions. (B) PET/MRI coregistered images in rhesus monkey brain under baseline (left) and blockade (right) conditions with
cpd 16.
removed the P-gp liability observed for the heterocyclic
sulfone derivatives and led to the identification of compound
16. The clinical evaluation of compound 16 will be published
in the near future.
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(5)
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SUPPORTING INFORMATION AVAILABLE Experimental
procedures for the preparation of compound 16 including analytical
and spectral characterization data (1H and 13C NMR, HR-MS, and
HPLC). This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. E-mail: wesley.blackaby@glpg.com.
Present Addresses: § Department of Medicinal Chemistry, Bio-
Focus, Chesterford Research Park, CB10 1Xl, United Kingdom.
(9)
ACKNOWLEDGMENT W.B. thanks Scott Wolkenberg for his
help in the preparation of this manuscript.
(10) The recent report of positive phase II results obtained with
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glycine transporters GlyT1 and GlyT2 in the rat CNS. Eur. J.
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TAC ðSUVÞ ¼ 1000 ꢀ TAC ðBqÞ
ꢀ weight ðkgÞ=injected tracer dose ðBqÞ
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