Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.05.074

SCH 58261 is a reported adenosine A_2A receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A₁ receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A_2A receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A_2A receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.

Full text of DOI:10.1016/j.bmcl.2008.05.074

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4199–4203
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective
adenosine A2A receptor antagonists
*
Unmesh Shah, Craig D. Boyle , Samuel Chackalamannil, Bernard R. Neustadt, Neil Lindo,
William J. Greenlee, Carolyn Foster, Leyla Arik, Ying Zhai, Kwokei Ng, Shiyong Wang,
Angela Monopoli, Jean E. Lachowicz
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SCH 58261 is a reported adenosine A2A receptor antagonist, which is active in rat in vivo models of Par-
kinson’s Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does
not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH
58261 which improve the A2A receptor binding selectivity as well as the pharmacokinetic properties of
SCH 58261. In particular, the quinoline 25 has excellent A2A receptor in vitro binding affinity and selec-
tivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 12 March 2008
Revised 15 May 2008
Accepted 16 May 2008
Available online 22 May 2008
Keywords:
Adenosine
A2A
A2A receptor
A2A antagonist
A2A receptor antagonist
SCH 58261
Parkinson’s Disease
Adenosine is the endogenous ligand for adenosine receptors A1,
2A, A2B, and A3, which are G-protein coupled receptors responsible
A
NH2
N
for a variety of physiological functions.1 In the CNS, adenosine
receptors exhibit a discrete localization pattern that includes dopa-
minergic projection fields such as the striatum. Colocalization with
D2 dopamine receptors in this region2 led to the hypothesis that
A2A receptors might be a target for Parkinson’s Disease (PD), a
debilitating motor disorder marked by degeneration of dopaminer-
gic neurons.3 In PD patients, the A2A antagonist istradefylline was
shown to improve the response rate and duration of therapeutic
efficacy of a subthreshold levadopa dose.4
N
N
O
N
SCH 58261 (1)
2A Ki = 2 nM
A1/A2A = 53
7
N
A
N
8
Ar het-Ar
Inner-ring Heteroaryls (C)
R
Substituted Biphenyls (A)
SCH 58261 is a reported A2A receptor antagonist5 with moder-
ate selectivity over the A1 receptor.6 It is active in vivo when dosed
intraperitoneally, but is not active upon oral administration.7 Our
goal was to optimize the structure–activity relationship (SAR) of
the SCH 58261 series to improve selectivity (>100-fold over A1)
and oral pharmacokinetics in order to discover orally active A2A
receptor antagonists with a low potential for A1 associated side
effects.
het-Ar
Outer-ring Heteroaryls (B)
Figure 1. A2A antagonist SCH 58261 and biaryl modification plans.
mal A2A in vitro profile while improving solubility and pharmaco-
kinetic properties. Biphenyl analogs (A) were synthesized as shown
in Scheme 1. Suzuki coupling with p-bromophenyl ethanol 2 fol-
lowed by mesylation produced biphenyl left-hand intermediates
3. The mesylate 3 was displaced by the anion of the SCH 58261 tri-
cyclic core 48 to yield the desired compounds 5–7.9 Outer hetero-
cyclics (B) were produced by two methods (Schemes 1 and 2).
Our initial plan (Fig. 1) was to produce biphenyl derivatives (A)
to develop an SAR for A2A selectivity. Secondary analogs of outer
(B) and inner (C) ring heterocycles could possibly maintain an opti-
* Corresponding author. Tel.: +1 908 740 3503; fax +1 908 740 7152.
E-mail address: craig.boyle@spcorp.com (C.D. Boyle).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.074

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U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4199–4203
NH2
O
N
N
4
N
N
NH2
N
HN
5-10
O
N
N
a, b
N
N
Br
Ar
Ar
OH
OMs
N
c
N
2
3
5:
6: Ar =
7:
8:
Ar = 3-pyridyl
Ar = Ph
9:
Ar = 4-MeO-3-pyridyl
p-MeOPh
10:
Ar = 4-Me-3-pyridyl
Ar =
p-CF3OPh
Scheme 1. Synthesis of biphenyl and outer heteroaryl analogs. Reagents and conditions: (a) ArB(OH)2, Pd(PPh3)4, K2CO3, toluene/H2O/EtOH, 120 °C, 16 h; (b) MsCl, Et3N,
CH2Cl2, 0 °C; (c) NaH, DMF, rt, 16 h.
N
N
a, b
c, d
e
e
Br
13
17
N
OTBS
N
OMs
OH
2
11
15
12
16
f
d
OH
OH
OMs
Br
14
N
N
g, f
h, d
e
HO
21
N
N
N
N
OMs
N
18
19
20
Scheme 2. Synthesis of heterobiaryl analogs. Reagents and conditions: (a) TBSCl, imidazole, DMF; (b) Tributyl(vinyl)tin, Pd(PPh3)4, toluene, 120 °C; (c) TBAF, THF; (d) MsCl,
Et3N, CH2Cl2, 0 °C; (e) 4, NaH, DMF, rt, 16 h; (f) Pyridine-3-boronic acid, Pd(PPh3)4, K2CO3, toluene/H2O/EtOH, 120 °C, 16 h; (g) Tf2O, pyridine; (h) LDA, 0 °C followed by DMF,
then NaBH4.
Compounds 8–10 were synthesized by the Suzuki coupling of
appropriate heterocyclic boronic acids with bromide 2, followed
by N-alkylation of the subsequently formed mesylates with the tri-
cyclic amine 4 (Scheme 1). The m-pyridyl analog 17 was prepared
by a similar route starting from the bromide 14 (Scheme 2). Stille
coupling was employed in the synthesis of the pyrazine intermedi-
ate 12 of compound 13 (Scheme 2). Inner heterocyclics (C) such as
compound 21 were synthesized in a reverse order of steps. The tri-
flate of hydroxypyridine 18 underwent Suzuki coupling to form the
biaryl intermediate 19. Chain extension provided the mesylate 20
(Scheme 2).
The SAR of biaryl analogs is summarized in Table 1. All of the
biaryl analogs had excellent A2A receptor affinity.10 Compared with
SCH 58261 (1), the biphenyl analogs (5–7) had improved selectiv-
ity for the A2A receptor, but did not improve oral activity. However,
incorporation of outer heteroaryl groups generally resulted in im-
proved pharmacokinetics11 as well as oral in vivo activity in the
haloperidol-induced catalepsy assay, a measure of A2A antagonist
activity in the basal ganglia.12 Specifically, compounds 8 and 10
had moderate rat plasma levels and were active orally at 1 h
post-dosing. Inner heterocyclics represented by compound 21 gen-
erally gave decreased A2A binding affinity and selectivity. Likewise,
m-biaryl analogs such as 17 did not improve upon the A2A selectiv-
ity of SCH 58261 and also had poor pharmacokinetics.
aqueous solubility was poor, and their oral pharmacokinetics suf-
fered from fast clearance. This resulted in a low duration of
in vivo activity in the oral catalepsy model. To address these issues,
quinoline analogs were designed as fused heteroaryl isosteres of
the biaryl moiety.
Bromoquinoline 22 was used as a starting material for most of
the quinoline targets (Scheme 3). Stille coupling and hydroboration
provided the alcohol 23, which was converted to 25 from the mes-
ylate 24. The common aldehyde intermediate 26 was also synthe-
sized from 23 via silyl protection and benzylic oxidation.
Aldehyde 26 proved to be a versatile intermediate in the syn-
thesis of quinoline analogs (Scheme 3). Wittig chain extension
and hydrogenation provided the ethyl intermediate 27. Aldehyde
26 was also reduced or treated with methyl Grignard reagent to
yield primary and secondary alcohols which were subsequently
alkylated to form the methoxyethoxy intermediates 29 and 31.
Reductive amination of aldehyde 26 and its methyl ketone analog
with morpholine gave the intermediates 33 and 36. A slightly dif-
ferent route was employed to synthesize the 2-morpholinoquino-
line analog (Scheme 4). The bis-chloroquinoline 38 was displaced
by morpholine, and the ethanol portion of intermediate 39 was
constructed via Stille coupling and hydroboration.
As shown in Table 2, the quinoline analogs generally exhibited
excellent A2A receptor binding affinity and selectivity over A1. Oral
rat pharmacokinetics were variable, but several compounds exhib-
ited good plasma exposure. Most of the quinoline derivatives also
Although the p-heterobiaryls 8 and 10 improved upon the A2A
selectivity of SCH 58261 and demonstrated oral activity, their

U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4199–4203
4201
Table 1
Structure–activity relationship of biaryl analogs
NH2
N
N
O
N
N
Ar
N
N
Compound #
Ar
A2A Kia (nM)
A1/A2A
109
k. sol.b
(l
M)
Rat AUCc
—
Catalepsyd
1 or 3 mpk po, 1 h/4 h
e
5
1.1
—
—
6
7
0.5
7.8
1.5
1.9
0.6
0.9
2124
100
255
283
257
372
<5
<5
<4
<5
<5
<4
0
30/5 (1 mpk)
20/0
MeO
67
351
0
F3CO
8
40/25 (1 mpk)
—/0 (3 mpk)
60/25
N
MeO
9
N
10
13
199
114
N
N
N
—/3 (3 mpk)
17
5.5
66
30
25
—
0
—
—
N
21
11.4
—
N
N
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6 h, 3 mpk, 20% HPbCD, po.11
d
e
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.
improved upon the solubility of their biaryl counterparts. How-
ever, the more soluble compounds such as 34, 35 and 37 tended
to be less active in the catalepsy assay, which could be due to a
lower ability of polar compounds to reach the striatum. The meth-
ylquinoline 25 had a good pharmacokinetic profile with sustained
plasma levels over 4 h (Fig. 2). The in vivo duration of compound
25 was supported by the catalepsy assay, as activity was demon-
strated at both 1 and 4 h post-dosing. Furthermore, quinoline 25
was dosed down to 1 mpk in the catalepsy assay and was also ac-
tive at the 4-h timepoint.
In conclusion, initial biaryl targets based on the SCH 58261 tem-
plate improved A2A receptor selectivity over A1, and outer hetero-
aryl analogs showed a modest pharmacokinetic improvement.
Quinoline isosteres maintained excellent in vitro properties while
improving upon the pharmacokinetics of SCH 58261. Ultimately,
the methylquinoline analog 25 proved to be a superior A2A receptor
antagonist in terms of binding affinity, selectivity, PK and oral
activity in the catalepsy assay. Further optimization of this series
of A2A receptor antagonists will be disclosed in future publications.
Acknowledgments
The authors thank Professors Ronald Breslow and Scott Rych-
novsky, Drs. Michael Graziano, John Hunter, John Piwinski, Andrew
Stamford, Catherine Strader and Geoffrey Varty for helpful discus-
sions. We also thank Drs. Mark Liang, Jesse Wong and Mr. Y. Jin for
providing the tricyclic intermediate 4. In addition, we thank Drs.
Charles McNemar, William Windsor, and Mr. Ashwin Ranchod for
providing solubility data. We also thank Drs. Pradip Das and Ben
Pramanik for obtaining analytical data.

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U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4199–4203
OMs
f
c
25
N
24
Br
OH
a, b
OTBS
N
N
d, e
O
22
23
N
26
OMs
OTBS
g, h, i, c
f
O
28
30
N
N
27
26
26
OMs
f
O
j, k, i, c
l, k, i, c
MeO
N
OTBS
29
31
O
N
f
f
OMs
32
O
MeO
O
N
34
35
OMs
m, i, c
N
N
OTBS
f, e
f
33
O
N
26
OMs
l, n, o, i, c
O
37
N
N
36
Scheme 3. Synthesis of quinoline analogs. Reagents and conditions: (a) Tributyl(vinyl)tin, Pd(Ph3P)4, DMF, 100 °C; (b) 9-BBN, THF; then aq NaOH, H2O2; (c) MsCl, Et3N,
CH2Cl2; (d) TBSCl, imidazole, DMAP, DMF; (e) SeO2, dioxane, 100 °C; (f) 4, NaH, DMF, rt, 16 h; (g) n-BuLi, THF, 0 °C, MePPh3Br; then 26; (h) H2, 10% Pd/C, MeOH; (i) TBAF, THF;
(j) NaBH4, MeOH; (k) NaH, DMF, BrCH2CH2OMe; (l) MeMgBr, THF, 0 °C; (m) Morpholine, AcOH, NaBH3CN, MeOH; (n) Dess–Martin periodinane, CH2Cl2, NaHCO3;
(o) Morpholine, AcOH, NaBH(OAc)3, DCE.
OMs
B.; Spalluto, G.; Pineda de Villatoro, M. J.; Zocchi, C.; Dionisotti, S.; Ongini, E. J.
Med. Chem. 1996, 39, 1164.
Cl
e
a, b, c, d
40
6. (a) Selectivity over A1 is necessary to avoid cardiac side effects.; (b) Hauser, R.
A.; Hubble, J. P.; Truong, D. D. Neurology 2003, 61, 297; (c) Francis, J. E.; Cash, W.
D.; Psychoyos, S.; Ghai, G.; Wenk, P.; Friedmann, R. C.; Atkins, C.; Warren, V.;
Furness, P.; Hyun, J. L.; Stone, G. A.; Desai, M.; Williams, M. J. Med. Chem. 1988,
31, 1014; (d) Sarges, R.; Howard, H. R.; Browne, R. G.; Lebel, L. A.; Seymour, P.
A.; Koe, B. K. J. Med. Chem. 1990, 33, 2240; (e) Also see Ref. 4.
N
N
Cl
N
O
39
38
Scheme 4. Synthesis of morpholine analog. Reagents and conditions: (a) Morpho-
line, K2CO3, DMF, 120 °C; (b) Tributyl(vinyl)tin, Pd2(dba)3, PtBu3, CsF, dioxane,
90 °C; (c) 9-BBN, THF; then aq NaOH, H2O2; (d) MsCl, Et3N, CH2Cl2, 0 °C; (e) 4, NaH,
DMF, rt, 16 h.
7. Ongini, E. Drug Dev. Res. 1997, 42, 63.
8. Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford, A. W.; Tulshian, D.;
Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz,
J.; Ng, K.; Feng, K.-I. Bioorg. Med. Chem. Lett. 2007, 17, 1376.
9. All of the final compounds in this publication were synthesized by the mesylate
alkylation of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
Scheme 1. A mixture of 7- and 8-alkylated products was formed. The N-8
alkylated analogs were generally inactive.
4 shown in
References and notes
1. Fredholm, B. B.; Abbracchio, M. P.; Burnstock, G.; Daly, J. W.; Harden, T. K.;
Jacobson, K. A.; Leff, P.; Williams, M. Pharmacol. Rev. 1994, 46, 143.
2. Augood, S. J.; Emson, P. C. Mol. Brain Res. 1994, 22, 204.
3. (a) Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 7238; (b) Schwarzschild, M. A., guest editor. Prog.
Neurobiol. 2007, 83, 261. Special Issue: Targeting Adenosine A2A Receptors in
Parkinson’s Disease and Other CNS Disorders.
4. Bara-Jimenez, W.; Sherzai, A.; Dimitrova, T.; Favit, A.; Bibbiani, F.; Gillespie, M.;
Morris, M. J.; Mouradian, M. M.; Chase, T. N. Neurology 2003, 61, 293.
5. (a) Zocchi, C.; Ongini, E.; Conti, A.; Monopoli, A.; Negretti, A.; Baraldi, P. G.;
Dionisotti, S. J. Pharmacol. Exp. Ther. 1996, 276, 398; (b) Baraldi, P. G.; Cacciari,
10. Binding Assay: Matasi, J. J.; Caldwell, J. P.; Hao, J.; Neustadt, B.; Arik, L.; Foster, C.
J.; Lachowicz, J.; Tulshian, D. B. Bioorg. Med. Chem. Lett. 2005, 15, 1333; footnote
11. Functional assays run on selected compounds throughout the A2A program
indicate that similar pyrazolotriazolopyrimidines are antagonists with Kb
values approximating the binding assay derived Ki values. In addition, affinity
for the rat A1 and A2A receptors did not differ from affinity for the human
receptor.
11. Procedure described in: Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.;
Broske, L.; Nomeir, A. A.; Lin, C.-C.; Cayen, M. N.; Barr, W. H. Drug Discov.
Today 1999, 4, 232. %CV values typically range from 10 to 30 in this assay
(n = 2).

U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4199–4203
4203
Table 2
Structure–activity relationship of quinoline analogs
NH2
N
N
O
N
N
Ar
N
N
a
Compound #
Ar
A2A Ki (nM)
A1/A2A
169
(l
M)
k. sol.b
Rat AUCc
1405
Catalepsyd
3 mpk po, 1 h/4 h
25
2.4
2.7
6
86/38
N
28
30
242
436
<2.5
12
450
68
43/38
0/0
N
OMe
O
2.8
1.5
N
OMe
e
O
O
32
1320
—
0
—
N
N
34
35
37
2.3
1.6
364
501
37
656
0/0
N
N
O
O
N
O
100
—
23/13
N
1.3
1.8
1278
2139
100
7489
28/13
N
O
N
40
—
6
—
N
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6 h, 3 mpk, 20% HPbCD, po.11
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.
d
e
ng/ml
nM
900
800
700
600
500
400
300
200
100
0
12. (a) Inhibition of haloperidol-induced catalepsy is an in vivo assay used to
evaluate Parkinson’s drugs (>30% inhibition is considered to be active in this
assay); (b) Mandhane, S. N.; Chopde, C. T.; Ghosh, A. K. Eur. J. Pharmacol. 1997,
328, 135; (c) Procedure described in Matasi, J. J.; Caldwell, J. P.; Zhang, H.;
Fawzi, A.; Cohen-Williams, M. E.; Varty, G. B.; Tulshian, D. B. Bioorg. Med. Chem.
Lett. 2005, 15, 3670.
13. The nephelometric (light scattering) method was used to determine the kinetic
solubility of compounds. The test compound (1.0 mg) was dissolved in DMSO
at 25 mM.
A serial dilution into DMSO was performed and 3 ll of the
compound in DMSO at various concentrations was added to the buffer (10 mM
phosphate, pH 7.4). Presence of precipitate was detected by nephelometry.
Solubility was defined as the highest concentration of material that did not
scatter light. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug
Deliv. Rev. 2001, 46, 3.
0
1
2
3
4
5
6
Time Post-Dose (hr)
Figure 2. Rat AUC of compound 25.