3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity

Article abstract of DOI:10.1016/j.bmcl.2012.02.003

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2- methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.

Full text of DOI:10.1016/j.bmcl.2012.02.003

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2514–2517
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity
⇑
Matthew J. Fisher , Ryan T. Backer, Vanessa N. Barth, Kim E. Garbison, Joseph M. Gruber,
Beverly A. Heinz, Smriti Iyengar, Sean P. Hollinshead, Anne Kingston, Steven L. Kuklish, Linglin Li,
Eric S. Nisenbaum, Steven C. Peters, Lee Phebus, Rosa Maria A. Simmons, Ellen van der Aar
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46258, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with
generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties
of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopro-
panecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral
administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which cor-
related with CNS receptor occupancy.
Received 3 January 2012
Revised 31 January 2012
Accepted 1 February 2012
Available online 9 February 2012
Keywords:
mGluR1
Ó 2012 Elsevier Ltd. All rights reserved.
Receptor occupancy
Formalin model
Glutamate is a nonessential amino acid that functions as an
excitatory neurotransmitter in the central nervous system (CNS).
Biological signaling via glutamate is accomplished by activation
of either ionotrophic GRIN (NMDA), GRIA (AMPA), GRIK (kainate)
or metabotropic (mGlu) receptors.1,2 The metabotropic glutamate
receptors comprise of a family of 8 Class-C G-protein coupled
receptors (GPCR) which are divided into three subfamilies based
on differences in molecular structure, pharmacology, and intracel-
lular signaling pathways. Group 1 mGlu receptors consist of
mGluR1 and mGluR5, which are predominantly expressed postsy-
this hypothesis comes from early preclinical studies demonstrating
that intrathecal injection of antisense mGlu1 oligonucleotides or
neutralizing antibodies can attenuate nociceptive responding in
multiple animal models of pain.8–11 While these initial data dem-
onstrated that blockade of mGluR1 signaling may have utility for
the treatment of chronic pain conditions, practical exploration
and subsequent exploitation of this finding required the identifica-
tion and refinement of bioavailable small molecule antagonists.
Structurally, type 3 GPCR’s have a large extracellular domain
containing an orthosteric binding site and a familiar 7-transmem-
brane domain found across GPCR’s. Initial strategies for the gener-
ation of competitive antagonists targeted the extracellular binding
site and consequently yielded compounds structurally similar to
glutamate (see compounds 1–3).12 These analogs provided a
means for in vitro studies but lacked the properties required for
predictable CNS penetration. They typically possessed low micro-
molar potency and sub-optimal subtype selectivity for meaningful
in vivo work.
napticaly and signal through Gaq G-proteins. Group 2 (mGluR2
and mGluR3) and Group 3 (mGluR4, 6, 7, 8) are expressed either
pre and/or post synaptically and inhibit adenylate cyclase through
coupling with Ga
i.3,4 Since the identification and characterization
of the mGlu receptors, significant effort has been expended to
understand the pharmacology and medicinal utility afforded by
this subclass of glutamate receptors.
Of the Group 1 mGlu receptors, considerable interest has fo-
cused on mGluR1 receptors because they are expressed in ascend-
ing nociceptive pathways, including peripheral nerves and sensory
regions of the spinal cord and brain. In addition, activation of
mGluR1 receptors has been shown to be critical for the induction
and maintenance of long-term increases in glutamatergic signaling
in nociceptive pathways which is postulated to contribute to the
reduction in pain threshold (i.e., allodynia), amplification of pain
responses (i.e., hyperalgesia) and a spread of pain sensitivity to
non-injured areas in clinical persistent pain states.5–7 Support for
CO2H
CO2H
CO2H
H3C
H3C
H
H
CO2H
H2N
CO2H
CO2H
1 (LY367385)
3 (s-ACUDA)
2 (AIDA)
In an effort to identify compounds structurally distinct from
amino acids, screening strategies employing functional readouts
were developed which afforded the opportunity to discover
⇑
Corresponding author. Tel.: +1 317 276 0632.
E-mail address: fisher_matthew_j@lilly.com (M.J. Fisher).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.003

M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2514–2517
2515
antagonists which engage sites other than the glutamate binding
domain.13–16 Over the years, this approach has yielded a number
of potent structurally distinct allosteric mGluR1 antagonists with
drug-like properties (see compounds 4–6).17–21 These tool com-
pounds have helped to solidify the role of mGluR1 in pain as well
as other interesting pharmacologies.22
During the course of our investigations into bioactive amides of
3-phenylaminoisothiazoles, we found that compound 7 (a mixture
of trans-enantiomers) had an IC50 of 32 nM in an in vitro functional
assay designed to detect allosteric antagonists of human
mGluR1.23 Herein we would like to report our structure activity
relationship (SAR) findings regarding the aryl portion of this mole-
cule and disclose both the pharmacokinetic (PK) and in vivo prop-
erties of one of our most potent molecules.
allowing the free amine to react with the acid chloride of 2-methyl
cypropanecarboxylate or by condensation of the isothiazole with
and an ester of 2-methylcyclopropane carboxylate in the presence
of trimethyl aluminum.
From an activity perspective, our first concern was to under-
stand if compound 7 displayed an enantiopreference with respect
to mGluR1 antagonistic activity. Towards this end, we prepared
both antipodes starting from the enantiopure cyclopropyl carbox-
ylates and the data for each is collected in Table 1.26–28 Compound
13, with the S,S configuration displayed an IC50 of 110 nM while
the R,R enantiomer 14 was significantly more potent with an IC50
of 9 nM. This finding allowed us to focus on the R,R configuration
for subsequent analogs.
Additional SAR reflecting modifications of the phenyl group are
captured in Table 2. Using compound 14 as a reference, removal of
the ring substituent afforded compound 15 which gave roughly a
7-fold loss in activity. Extension of the methoxy group by one atom
provides the ethoxy analog 16, which was roughly 10-fold less po-
tent than 3. Addition of fluorine to the ring of compound 14 gives
rise to 17 which afforded similar mGluR1 activity. Exchange of the
methoxy with fluoro yielded compound 18 which displayed a 10-
fold erosion of activity relative to 14 while the chloro analog 19
and bromo analog 20 were essentially equipotent with regard to
mGluR1 potency. The one example of double substitution by halo-
gen caused a slight reduction in potency as exemplified by 21. The
O
O
F
N
N
N
N
H
N
F
N
N
N
HO
5
4
O
N
O
6
Table 1
mGluR1 antagonist activity relative to cyclopropyl configuration
N
O
S
O
N
S
N
CH3
H
CH3
N
R
CH3O
7
O
mGluR1 IC50 32 nM
Construction of the desired molecules begins as shown in
Compound
R
mGlu1a (nM)
32 12
Scheme 1.24 Condensation of a variety of substituted phenyl ni-
triles 8 with propionitrile 9 afforded the b-amino acrylonitriles
10 in good yield. Reaction of nitriles 10 with thioacetamide yielded
the desired isothiazole precursors 11. Cyclization of these interme-
diates was accomplished by oxidation with hydrogen peroxide
which gave rise to aminoisothiazoles 12.25 These materials were
converted into the desired product amides 7 and 13–23 by either
7
S
R
13
14
110 99
S
9
2
R
a
Represents the average ( SEM) of at least three separate determinations.
NH2
CN
CN
S
a
CN
Table 2
R
+
R
SAR findings for phenyl ring substitution
b
8
9
O
10
S
N
N
H
S
NH2
N
NH2
c
R1
NH2
R
R
R2
11
12
Compound
R1
R2
hmGlu1 (nM)a
hmGlu5 (nM)a
O
S
14
15
16
17
18
19
20
21
22
23
OCH3
H
OCH2CH3
OCH3
F
Cl
Br
Cl
CF2CH3
OH
H
H
H
F
H
H
H
Cl
H
H
9
2
158 65
>12500
d
N
NH
65 32
92
7
9
2
19
5
R
159 43
>12500
1220 182
730 157
6650 1614
>12500
100 69
9
7
2
2
7 and 13-23
39 15
67 21
138 36
Scheme 1. Reagents and conditions: (a) 1 N NaoBut in THF, rt, 4–18 h, 50–85%; (b)
thioacetamide, HCl dioxane, rt, 2–4 h; (c) MeOH, 30% H2O2, rt, 2–8 h (steps b and c
ꢀ30–60%); (d) Me3Al, toluene, RO2Et, 50 °C, 18 h,60–80% or pyridine, ROCl, DCM,
3 h, 60–92%.
>12500
a
Represents the average ( SEM) of at least three separate determinations.

2516
M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2514–2517
difluoroethyl analog 22 was similar in potency to the ethoxy ana-
log 16 and the hydroxyl analog 23 was substantially less active
than its methoxy congener 14. Compounds generally showed mod-
erate to good selectivity for mGluR1 with the exception of com-
pound 16, which was slightly more potent as an mGluR5
antagonist.
100
80
60
40
20
0
In an effort to establish the utility of this series for understand-
ing in vivo mGluR1 pharmacology, we chose to evaluate the spe-
cies receptor selectivity and in vivo exposure characteristics of
compound 14. Results from an in vitro rat mGluR1 receptor assay,
analogous to the one described for determining human mGluR1
receptor activity,23 demonstrated compound 14 was a comparably
potent antagonist of the rat mGluR1 receptor having an IC50 of
0.9 nM. Compound 14 was also checked across a panel of mGlu
receptors (mGluR 3, 4, 7, and 8) as well as broadly through a panel
of 38 receptors and ion channels at CEREP™ and was found to have
no additional cross reactivities. The plasma pharmacokinetic pro-
files of 3 in Sprague Dawley rats was next determined by measur-
ing plasma levels resulting from both intravenous (IV) and oral
administration of 3 and 10 mg/kg, respectively. The oral doses
were delivered as a suspension consisting of methylcellulose
A400 1% plus antifoam 0.1% and the IV doses were delivered as a
solution in phosphate buffer 25 mmol/L (pH 3) plus 5% solutol
HS15 and 5% pharmasolve. The data indicate that compound 14
was rapidly absorbed, with maximum plasma concentrations
(tmax) attained at 1.0 h after oral dosing. The Cmax and AUC0–24 h
after oral dosing were 1050 ng/mL and 3240 ng h/mL, respectively.
The IV and oral elimination half-life was 0.41 and 1.24 h, respec-
tively. The observed clearance was 35.9 mL/min/kg and the volume
of distribution was 1.27 L/kg. The absolute oral bioavailability was
55.5%. In similar studies, we determined that brain concentration
profiles corresponded to those found for plasma, with a brain to
plasma ratio of 0.2.
0.1
1
10
100
Dose (mg/kg) p.o.
Figure 1. Oral dose–response curve for 14 mGluR1 RO. For each group n = 4 except
for the 10 mg/kg dose, where n = 3. Error bars represent SEM.
1000
vehicle
1 mg/kg
3 mg/kg
10 mg/kg
800
30 mg/kg
60 mg/kg
600
*
*
400
*
*
200
0
Early phase
Late phase
Figure 2. Effects of 14 on formalin-induced paw-licking behavior in fasted male
Sprague Dawley rats 1 h after oral administration of drug (1, 3, 10, 30, 60 mg/kg,
N = 8 per group). Early phase behavior is measured from 0–5 min and late phase
behavior is measured from 11–40 min after intraplantar injection of 50 ll of 5%
Having demonstrated acceptable peripheral and brain exposure,
we next sought to determine if compound 14 would afford mea-
surable CNS receptor occupancy (RO) following oral administra-
tion.29,30 Accordingly, a cohort of fasted Sprague Dawley rats
were dosed orally with 14 and a similar cohort dosed with vehicle
(1% methyl cellulose). After one hour, both groups received a
formalin into the right hindpaw. Data are expressed as paw-licking events
(mean SEM). ⁄p <0.05 significantly different from vehicle group.
Finally, as efficacy in the formalin model can be confounded by
impairment, we subjected compound 14 to a standard evaluation
in the rotorod test for motor function.36 At an oral dose of
60 mg/kg, a dose that is 8.5Â the formalin absolute ED50, we found
that compound 14 did not induce any deficits in rotorod
30 lg/kg intravenous bolus of a competing mGluR1 antagonist,
compound 6, which was used as a tracer.31,32 Twenty minutes fol-
lowing administration of the tracer, animals were sacrificed and
the cerebellum (mGlu1 receptor-rich brain region) and frontal cor-
tex (little to no mGlu1 receptor) were dissected and weighed. Each
tissue sample was then evaluated for concentrations of compound
6 and 14 by mass spectrometry and the concentrations from each
group compared. The determined RO was calculated using the
well-established ratio method which employs a region of high
receptor density, representative of total binding (in this case the
cerebellum), normalized by an area without or with very low levels
of receptor (in this case the frontal cortex).33 A dose-occupancy
experiment with 14, with doses of 0.3, 1, 3, 10, 30, and 60 mg/kg,
demonstrated that compound 14 afforded good occupancy (ED50
value of 3.7 mg/kg) at the doses examined (see Fig. 1).
1 hour
2 hours
3 hours
4 hour s
50
Baseline
Training = 40.0 +/- 0.0 sec
40
30
20
10
0
We next examined the activity of compound 14 in the formalin
model of persistent pain.34 In this assay, oral administration of 14,
1 h prior to treatment of male Harlan Sprague Dawley rats with an
intraplantar injection of formalin, caused dose dependent attenua-
tion of late phase formalin-induced paw-licking behavior (see
Fig. 2). Statistically significant effects were observed between the
dose range of 3–60 mg/kg po and the absolute ED50 for attenuation
of late phase formalin-induced paw-licking behavior was deter-
mined to be 7 mg/kg. Interestingly, the absolute ED50 for efficacy
in the formalin model was comparable to the ED50 afforded by
the RO assay suggesting positive correlation between central occu-
pancy of mGluR1 and efficacy in this model.35
vehicle
60 mg/kg
Figure 3. Effects of 14 on rotorod performance at 60 mg/kg in fasted male Sprague
Dawley rats at 1, 2, 3 and 4 h after oral administration of drug (N = 8 per group).
Baseline performance was 40 s. Data are expressed as time on rotorod in seconds
(mean SEM).

M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2514–2517
2517
22. Ferraguti, F.; Crepaldi, L.; Nicoletti, F. Pharmacol. Rev. 2008, 60, 536.
performance for up to 4 h (see Fig. 3). This data supports the notion
that the efficacy observed in the formalin model was due to the
specific compound related blockade of mGluR1 and not the result
of motor impairment.
23. The compounds of this Letter were evaluated in stable AV12 clonal cell lines
expressing recombinant human mGlu1 receptors. Responses mediated by the
mGlu receptor were determined by changes in intracellular calcium
concentrations measured by a fluorescent calcium sensitive dye Fluo-3 using
a 96 channel fluorometric imaging plate reader. The antagonist effects of
compounds were quantified by comparing the peak fluorescence response to
glutamate in the presence and absence of compound. The assay window was
defined as the maximal response obtained by glutamate at its predetermined
EC90% concentration minus the response obtained by buffer alone. Antagonist
effects were calculated as a percent of the assay window. IC50 values were
calculated using a 4 parameter logistic curve fitting program.
24. Backer, R. T.; Fisher, M. J.; Kuklish, S. L.; Hollinshead, S. P.; Smith, E. C. R.;
Takeuchi, K. WO2008/103185A2.
25. Kuklish, S. L.; Fisher, M. J.; Kempema, A. M.; Mauldin, S. C.; Merschaert, A.;
Backer, R. T. Abstracts of Papers, 233rd ACS National Meeting, Chicago, IL,
United States, March 25–29, 2007.
26. Delhaye, L.; Stevens, C.; Merschaert, A.; Delbeke, P.; Brione, W.; Tilstam, U.;
Borghese, A.; Geldhof, G.; Diker, K.; Dubois, A. Org. Process Res. Devel. 2007, 11,
1104.
In summary, we have disclosed a novel series of isothiazole
amides with potent mGluR1 antagonist activity. One representa-
tive compound (14) displayed good peripheral and central PK
properties. This compound showed dose responsive CNS receptor
occupancy that correlated with activity in the formalin model of
persistent pain. These data are consistent with other reports of
antagonists of mGluR1 demonstrating efficacy in various pain
states.37–40 Additional data regarding both preclinical and clinical
characterization of molecules within this series will be reported
in due course.
References and notes
27. Delhaye, L.; Merschaert, A.; Delbeke, P.; Brione, W. Org. Process Res. Devel. 2007,
11, 689.
28. Gajewski, J. J.; Squicciarini, M. P. J. Am. Chem. Soc. 1989, 111, 6717.
29. Chernet, E.; Martin, L. J.; Li, D.; Need, A. B.; Barth, V. N.; Rash, K. S.; Phebus, L. A.
Life Sci. 2005, 78, 340.
30. Barth, V. N.; Chernet, E.; Martin, L. J.; Need, A. B.; Rash, K. S.; Morin, M.; Phebus,
L. A. Life Sci. 2006, 78, 3007.
1. Foster, A. C.; Kemp, J. A. Curr. Opin. Pharmacol. 2006, 6, 7.
2. Meldrum, B. S. J. Nutr. 2000, 130, 1007S.
3. Schoepp, D. D.; Bockaert, J.; Sladeczek, F. Trends Pharm. Sci. 1990, 11, 508.
4. Schoepp, D. D.; Conn, P. J. Trends Pharm. Sci. 1993, 14, 13.
5. Lesage, A. S. J. Curr. Neuropharmacol. 2004, 2, 363.
31. Lavreysen, H.; Pereira, S. N.; Leysen, J. E.; Langlois, X.; Lesage, A. S. J.
Neuropharmacol. 2004, 46, 609.
32. Mabire, D.; Coupa, S.; Adelinet, C.; Poncelet, A.; Simonnet, Y.; Venet, M.;
Wouters, R.; Lesage, A. S. J.; Van Beijsterveldt, L.; Bischoff, F. J. Med. Chem. 2005,
48, 2134.
33. Wadenberg, M.-L. G.; Kapur, S.; Soliman, A.; Jones, C.; Vaccarino, F.
Psychopharmacology 2000, 150, 422.
34. Moore, S. A.; Nomikos, G. G.; Dickason-Chesterfield, A. K.; Schober, D. A.;
Schaus, J. M.; Ying, B.-P.; Xu, Y.-C.; Phebus, L.; Simmons, R. M. A.; Li, D.; Iyengar,
S.; Felder, C. C. Proc. Nat. Acad. Sci. 2005, 102, 17852.
6. Bleakman, D.; Alt, A.; Nisenbaum, E. S. Semin. Cell Devel. Boil. 2006, 17, 592.
7. Schkeryantz, J. M.; Kingston, A. E.; Johnson, M. P. J. Med. Chem. 2007, 50, 2563.
8. Young, M. R.; Blackburn-Munro, G.; Dickinson, T.; Johnson, M. J.; Anderson, H.;
Nakalembe, I.; Fleetwood-Walker, S. M. J. Neurosci. 1998, 18, 10180.
9. Fundytus, M. E.; Henry, J. L.; Dray, A.; Coderre, T. J. Prog. Pain Res. Man. 2000, 16
(Proceedings of the 9th World Congress on, Pain, 1999), 343.
10. Fundytus, M. E.; Yashpal, K.; Chabot, J.-G.; Osborne, M. G.; Lefebvre, C. D.; Dray,
A.; Henry, J. L.; Coderre, T. J. Br. J. Pharmacol. 2001, 132, 354.
11. Noda, K.; Anzai, T.; Ogata, M.; Akita, H.; Ogura, T.; Saji, M. Brain Res. 2003, 987,
194.
35. Suzuki, G.; Kawagoe-Takaki, H.; Inoue, T.; Kimura, T.; Hikichi, H.; Murai, T.;
Satow, A.; Hata, M.; Maehara, S.; Ito, S.; Kawamoto, H.; Ozaki, S.; Ohta, H. J.
Pharmacol. Sci. 2009, 110, 315.
36. Iyengar, S.; Webster, A. A.; Hemrick-Luecke, S. K.; Xu, J.; Simmons, R. M. A. J.
Pharmacol. Exp. Ther. 2004, 311, 576.
12. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1431.
13. Litschig, S.; Gasparini, F.; Rueegg, D.; Stoehr, N.; Flor, P. J.; Vranesic, I.; Prezeau,
L.; Pin, J.-P.; Thomsen, C.; Kuhn, R. Mol. Pharmacol. 1999, 55, 453.
14. Lavreysen, H.; Janssen, C.; Bischoff, F.; Langlois, X.; Leysen, J. E.; Lesage, A. S. J.
Mol. Pharmacol. 2003, 63, 1082.
37. More, L.; Gravius, A.; Pietraszek, M.; Belozertseva, I.; Malyshkin, A.; Shekunova,
E.; Barberi, C.; Schaefer, D.; Schmidt, W. J.; Danysz, W. Behav. Pharmacol. 2007,
18, 273.
15. Gasparini, F.; Kuhn, R.; Pin, J.-P. Curr. Opin. Pharmacol. 2002, 2, 43.
16. Hemstapat, K.; de Paulis, T.; Chen, Y.; Brady, A. E.; Grover, V. K.; Alagille, D.;
Tamagnan, G. D.; Conn, P. J. Mol. Pharmacol. 2006, 70, 616.
38. Zhu, C. Z.; Baker, S.; El-Kouhen, O.; Lehto, S. G.; Hollingsworth, P. R.; Gauvin, D.
M.; Hernandez, G.; Zheng, G. Z.; Chang, R.; Moreland, R. B.; Stewart, A. O.;
Brioni, J. D.; Honore, P. Eur. J. Pharmacol. 2008, 580, 314.
39. El-Kouhen, O.; Lehto, S. G.; Pan, J. B.; Chang, R.; Baker, S. J.; Zhong, C.;
Hollingsworth, P. R.; Mikusa, J. P.; Cronin, E. A.; Chu, K. L.; McGaraughty, S. P.;
Uchic, M. E.; Miller, L. N.; Rodell, N. M.; Patel, M.; Bhatia, P.; Mezler, M.; Kolasa,
T.; Zheng, G. Z.; Fox, G. B.; Stewart, A. O.; Decker, M. W.; Moreland, R. B.; Brioni,
J. D.; Honore, P. Br. J. Pharmaol. 2006, 149, 761.
17. Owen, D. R. ACS Chem. Neurosci. 2011, 2, 349.
18. Layton, M. E. Curr. Top. Med. Chem. 2005, 5, 859.
19. Sasikumar, T. K.; Li, Q.; Burnett, D. A.; Greenlee, W. J.; Li, C.; Heimark, L.;
Pramanik, B.; Grilli, M.; Bertorelli, R.; Lozza, G.; Reggiani, A. Bioorg. Med. Chem.
Lett. 2009, 19, 3199.
20. Owen, D. R.; Dodd, P. G.; Gayton, S.; Greener, B. S.; Harbottle, G. W.; Mantell, S.
J.; Maw, G. N.; Osborne, S. A.; Rees, H.; Ringer, T. J.; Rodriguez-Lens, M.; Smith,
G. F. Bioorg. Med. Chem. Lett. 2007, 17, 486.
40. Kohara, A.; Nagakura, Y.; Kiso, T.; Toya, T.; Watabiki, T.; Tamura, S.; Shitaka, Y.;
Itahana, H.; Okada, M. Eur. J. Pharmacol. 2007, 571, 8.
21. Wu, W.-L.; Burnett, D. A.; Domalski, M.; Greenlee, W. J.; Li, C.; Bertorelli, R.;
Fredduzzi, S.; Lozza, G.; Veltri, A.; Reggiani, A. J. Med. Chem. 2007, 50, 5550.