Synthesis and pharmacological characterization of two novel, brain penetrating P2X7 antagonists

Article abstract of DOI:10.1021/ml400040v

The synthesis and preclinical characterization of two novel, brain penetrating P2X₇ compounds will be described. Both compounds are shown to be high potency P2X₇ antagonists in human, rat, and mouse cell lines and both were shown to

Full text of DOI:10.1021/ml400040v

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Letter
Synthesis and Pharmacological Characterization
of two Novel, Brain Penetrating P2X7 Antagonists
Michael A Letavic, Brian Lord, Francois Bischoff, Natalie A Hawryluk, Serge Pieters, Jason C Rech,
Zachary Sales, Adriana I Velter, Hong Ao, Pascal Bonaventure, Victor Contreras, Xiaohui Jiang, Kirsten
L Morton, Brian Scott, Qi Wang, Alan D Wickenden, Nicholas Iain Carruthers, and Anindya Bhattacharya
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/ml400040v • Publication Date (Web): 12 Mar 2013
Downloaded from http://pubs.acs.org on March 13, 2013
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Synthesis and Pharmacological Characterization of two Novel, Brain
Penetrating P2X7 Antagonists
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Michael A. Letavic, Brian Lord, Francois Bischoff, Natalie A. Hawryluk, Serge Pieters, Jason C.
Rech, Zachary Sales, Adriana I. Velter, Hong Ao, Pascal Bonaventure, Victor Contreras, Xiao-
hui Jiang, Kirsten L. Morton, Brian Scott, Qi Wang, Alan D. Wickenden, Nicholas I. Car-
ruthers and
Anindya Bhattacharya
Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121-1126, United States
KEYWORDS P2X7, neuro-inflammation, depression.
ABSTRACT: The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be
described. Both compounds are shown to be high potency P2X7 antagonists in human, rat and mouse cell lines and
both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular
interest as a probe compound for the pre-clinical assessment of P2X7 blockade in animal models of neuro-
inflammation.
The P2X7 ion channel is a member of a large puri-
noreceptor family that includes both P2X ionotropic and
P2Y metabotropic receptors.1 There are seven known
P2X receptor subtypes, and of that group, P2X7 has been
shown to be involved in the release pro-inflammatory
cytokines, including IL-1β.2 As such, numerous reports
have appeared in the literature describing the role of
P2X7 in a variety of pro-inflammatory disease states in-
cluding pain, osteoarthritis, rheumatoid arthritis and
pathology associated with neuro-inflammation such as in
epilepsy, multiple sclerosis and a variety of neuro-
degenerative states including Alzheimer’s disease.3 Giv-
en that the P2X7 receptor is expressed in the CNS on as-
trocytes and microglial cells, and that the expression and
activation of P2X7 in glial cells may regulate glutamate
and IL-1β release, our interest in this target has focused
on the role of P2X7 in neuro-immune modulation. To
that end, it has been shown by various groups that the
pro-inflammatory cytokine IL-1β is involved in chronic
stress models of affective disorders.4-7 Furthermore,
P2X7 antagonism has been reported to be efficacious in
animal models of mood disorders and mouse/human
genetics study link P2X7 locus to mood disorders.8,9 We
were particularly interested in recent reports showing
evidence that IL-1 receptor blockade may be an effective
approach for the treatment of depression, suggesting
that a brain-penetrating P2X7 antagonist that blocked
IL-1β release in glial cells might be efficacious in mood
disorders.10
ed by inhibition of BzATP induced IL1-β release in hu-
man peripheral blood monocytes (pA2’s=8.8 and 8.0).
Pfizer also reported on a series of 2-chlorobenzamides
discovered via high throughput screening. Compound 3
was reported to be a relatively weak screening hit (P2X7
Yo-Pro IC50=1.1ꢀM), however medicinal chemistry ef-
forts lead to the identification of an analog (CE-224,535),
a very potent P2X7 antagonist that became a clinical can-
didate.14 Pfizer recently reported clinical results with
CE-224,535 in rheumatoid arthritis patients inadequate-
ly controlled by methotrexate.15
While the compound did not show efficacy in a three
month rheumatoid arthritis trial it is of note that Pfizer
reported that the compound exposure exceeded the
amount required for sustained inhibition of P2X7 (as
measured by IL-1β inhibition) for the entire three month
period. This data indicates that P2X7 inhibition is un-
A wide variety of P2X7 antagonists have been disclosed
over the past several years11 including numerous inter-
esting benzamides. Some early examples of drug-like
P2X7 antagonists disclosed by the Astra-Zeneca group
are the adamantyl-based compounds 112 and 213 shown
below. Both are potent P2X7 antagonists as demonstrat-
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likely to be a viable approach to the treatment of rheu- Similarly, compound 8 was prepared from 2-tert-butyl
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8
matoid arthritis; however it also indicates that sustained
inhibition of P2X7 in humans is not likely to be plagued
with mechanism-based adverse events.
5-methyl 3,4-dihydroisoquinoline-2,5(1H)-dicarboxylate
and the amine 12, which was formed by reaction of cy-
clohexanone with 1-phenylpiperazine as shown in
Scheme 2.
Examples of other interesting small, drug-like P2X7 an-
tagonists include the imidazolidinecarboxamides and
In vitro data for compounds 7 and 8 are detailed on Ta-
ble 1. Both compounds are potent P2X7 antagonists in
human and rodent cell lines and both compounds show
inhibition of Bz-ATP induced IL-1β secretion in human
peripheral blood monocytes and in human whole blood.
Because both compounds have good functional activity
and binding affinity in rat, we chose to further character-
ize these compounds in vivo with the intention of using
one or both of these as tool compounds for pharmacody-
namic studies.
pyroglutamates
recently
reported
by
Glaxo
SmithKline.16,17 While these compounds are potent hu-
man P2X7 antagonists, they also have some activity at
the rat P2X7 receptor and therefore could be used for
pre-clinical efficacy studies. The authors report that
brain penetrating P2X7 antagonists such as those shown
below are efficacious in pre-clinical pain models.
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Scheme 2. Synthesis of Compound 8a
Our interest in P2X7 antagonists focused on the identifi-
cation of potent, brain penetrating compounds with high
affinity for both the rat and human P2X7 in order to as-
sess their utility for the treatment of CNS disorders, in-
cluding depression. Towards this end, we now report the
discovery of N-((4-(4-phenyl-piperazin-1-yl)tetrahydro-
2H-pyran-4-yl)methyl)-2-(phenyl-thio) nicotinamide (7)
and
2-methyl-N-((1-(4-phenylpiperazin-1-
yl)cyclohexyl)methyl)-1,2,3,4-tetrahydroisoquinoline-5-
carbox-amide (8). These compounds were identified
after extensive medicinal chemistry efforts following an
HTS campaign that showed that simple N-
(cyclohexylmethyl)benzamides were weak P2X7 antago-
nists. The compounds were synthesized as shown in
Schemes
1
and 2.
For compound 7, 2-
(phenylthio)nicotinic acid was first converted to the acid
chloride 9. Next, dihydro-2H-pyran-4(3H)-one was
condensed with 1-phenylpiperazine and potassium cya-
nide then reduced to form the amine 10. Condensing 9
and10 then provided compound 7 in reasonable overall
yield.
aReagents and conditions: (a) methanol, H2O, NaOH, 100%, (b) KCN,
H2O, pH=3, (c) lithium aluminum hydride, tetrahydrofuran, 75%, (d)
BOP, triethyl amine, dichloromethane, 77%, (e) Trifluoroacetic acid, (f)
formaldehyde, sodium triacetoxyborohydride, 74%.
Scheme 1. Synthesis of Compound 7a
During the course of this characterization we discovered
that compound 8 is a high affinity SERT inhibitor, both
in human and rat (Table 1). Both compounds were also
screened in a commercial panel of 50 receptor, ion chan-
nel and transporter assays (CEREP, www.cerep.com) at 1
ꢀM. Compound 7 had a <50% effect at all targets tested,
whereas compound 8 had >50% inhibition on human
NK2 (68% inhib.), human DAT (93% inhib.) and r NaCH
(54% inhib.) IC50’s were generated for DAT (290 nM)
and r NaCH (910 nM). Recognizing that the SERT affini-
ty observed with 8 may be an issue when attempting to
assess the antidepressant effects of our P2X7 inhibitors,
most of our subsequent efforts were focused on com-
pound 7, however we continued to profile both lead mol-
ecules in order to assess their ability to distribute into
the brain.
aReagents and conditions: (a) oxalyl chloride, dichloromethane, dime-
thylformamide, 100%, (b) KCN, H2O, pH=3, (c) lithium aluminum hy-
dride, tetrahydrofuran, 75%, (d) dichloromethane, 53%.
Prior to any in vivo work, we obtained preliminary
DMPK and developability measurements for each com-
pound. The data are shown in Table 2. Both compounds
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are relatively drug-like with reasonable physical proper-
ties, solubility, protein binding, and permeability, how-
1
2
3
4
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7
ever both suffer from very high extraction ratios in hu-
man and rat liver microsomes indicating that they are
very unlikely to be suitable for oral delivery. Because
sub-cutaneous dosing is preferred for many in vivo mod-
els, we decided to assess the plasma and brain exposures
following sub-cutaneous dosing.
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Table 1. In Vitro Pharmacology for Compounds 7 and 8.
human
FLIPR
pIC50
rat
mouse
FLIPR pIC50
human pKi
rat pKi
rat/human
SERTe pKi
(nM)
human
PBMC
pIC50
human
WB pIC50
c
d
f
FLIPR pIC50
b
a
7
8.3+0.08
7.7+0.07
7.2+0.08
7.8+0.1
7.5+0.1
7.1+0.2
7.9+0.08
7.9+0.08
8.7+0.0
8
5.5/n.d.
7.6+0.07
7.4+0.07
6.7+0.07
8
9.1+0.0
7
7.7 (n=2)/7.8
6.7+0.09
ahuman peripheral blood monocyte pIC50 for IL-1b inhibition , bhuman FLIPR pIC50 measured in a Ca2+ flux assay, crat FLIPR pIC50 measured in a Ca2+
flux assay, dmouse FLIPR pIC50 measured in a Ca2+ flux assay, erat and human SERT Ki, human whole blood pIC50, all data are the result of at least
f
three assays run in triplicate + SEM.
Table 2. Physical Properties and In Vitro DMPK Parameters for Compounds 7 and 8.
MW
c log P
human
ERa
rat ERa
mouse
ERa
human/rat
ppbb
Caco-2
A to B/B to
Ac
brain pbd
Solubility pH2/pH7e
7
488.7
446.6
4.3
5.1
>0.95
0.90
>0.92
0.86
>0.93
0.90
97.8/97.1
83.5/95.6
--
98.3
97.6
400/31
95/90
8
11/2.1
ahuman, rat or mouse extraction ratio as measured in a microsomal preparation, bhuman or rat protein binding reported as % bound, cPapp reported in
units of cm/sec x 10-6 (data generated at CEREP, www.cerep.com), drat brain protein binding reported as % bound, eReported in ꢀM.
Figure 1. Ex Vivo P2X7 Receptor Occupancy,
Plasma and Brain Levels with Compound 7 (30
mg/kg) in Rat Brain: Time Dependency after
Subcutaneous Administration (n = 3 per time
point ± SEM).
Figure 2. Ex Vivo P2X7 Receptor Occupancy,
Plasma and Brain Levels with Compound 8 (10
mg/kg) in Rat Brain: Time Dependency after
Subcutaneous Administration (n = 3 per time
point ± SEM).
10000
1000
100
100
90
80
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60
50
40
30
20
10
0
Initial experiments are shown in Figures 1 and 2. In the-
se experiments, the compound was dosed subcutaneous-
ly (s.c.) and plasma and brain concentrations were
measured over time, along with central P2X7 receptor
occupancy as assessed by ex vivo autoradiography. The
results for compound 7 are shown in Figure 1. High
P2X7 receptor occupancy was achieved following a single
dose of 30 mg/kg s.c. and greater than >50% occupancy
remained for 2 hours at this dose, indicating robust tar-
get engagement. Similar results were seen with 10
mg/kg s.c. of compound 8 (Figure 2).
Plasma Exposure
Brain exposure
P2X7 Receptor Occupancy
0
1
2
3
4
5
6
7
Time (hr)
The dose dependency of central receptor occupancy was
assessed in a second series of experiments (Figures 3 and
4). Central occupancy was measured at the tmax for each
compound (15 min for Compound 7 and 120 min for
Compound 8; data not shown). Compound 7 had an
ED50 for occupancy of 2.5 mg/kg whereas compound 8
had a nearly 10-fold lower ED50 of 0.3 mg/kg. In sepa-
rate ex -vivo autoradiography studies compound 8 was
10000
1000
100
100
90
80
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60
50
40
30
20
10
Plasma Exposure
Brain Exposure
P2X7 Receptor Occupancy
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compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
determined to have ED50 for SERT occupancy of 24
mg/kg, indicating that SERT target engagement in rat
was not significant at doses where robust P2X7 receptor
occupancy was observed.
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8
AUTHOR INFORMATION
Corresponding Author
Figure 3. Ex Vivo P2X7 Receptor Occupancy with
Compound 7 in Rat Brain: Dose Dependency Fol-
lowing Subcutaneous Administration (n = 3 per
dose ± SEM). P2X7 occupancy was measured 15
min after drug administration.
*Corresponding
author.
E-mail
address
mletavic@its.jnj.com (M. A. Letavic).
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
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ABBREVIATIONS
IL-1β interleukin-1β, Bz-ATP benzoyl adenosine triphos-
phate, SERT serotonin transporter, DAT dopamine trans-
porter.
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In conclusion, we have demonstrated that compounds 7
and 8 are high affinity rat, mouse and human P2X7 re-
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DMPK properties suitable for pre-clinical pharmacody-
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ASSOCIATED CONTENT
Supporting Information. Supporting information in-
cludes detailed synthetic procedures for all intermediates
and products and descriptions of assays used to characterize
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