Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric mGluR5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2012.08.053

1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.

Full text of DOI:10.1016/j.bmcl.2012.08.053

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6454–6459
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric
mGluR5 antagonists
Manuel Koller a, , David A. Carcache a, David Orain a, Peter Ertl a, Dirk Behnke a, Sandrine Desrayaud a,
⇑
Grit Laue a, Ivo Vranesic b
a Novartis Institutes for BioMedical Research, Global Discovery Chemistry, 4002 Basel, Switzerland
b Novartis Institutes for BioMedical Research, Neuroscience Research, 4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Var-
iation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical
parameters for optimization of the aqueous solubility while retaining high in vitro potency.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 July 2012
Revised 10 August 2012
Accepted 13 August 2012
Available online 21 August 2012
Keywords:
Glutamate
Excitatory amino acid
Metabotropic glutamate receptor
mGluR5
Negative allosteric modulator
1H-pyrrolo[2,3-c]pyridine-7-carboxamides
Glutamate is the predominant excitatory neurotransmitter in
the mammalian brain and acts at several ionotropic (AMPA, kai-
nate and NMDA) and metabotropic glutamate receptor (mGluR)
subtypes. Whereas the ionotropic receptors mediate fast synaptic
transmissions, their metabotropic counterparts work in a modulat-
ing fashion on synaptic signaling. The eight known mGluR sub-
types are divided into three groups, based on their sequence
similarities, effector coupling and agonist/antagonist selectivity.
Group I comprises mGluR1 and mGluR5, both positively coupled
to phosphoinositide hydrolysis via activation of phospholipase C.
Group II consists of mGluR2 and 3, both of them negatively coupled
to cAMP production via adenylyl cyclase, and group III includes
mGluR4, 6, 7 and 8 which are also negatively coupled to cAMP pro-
duction. mGlu5 receptors are strongly expressed in the striatum,
hippocampus and cerebral cortex and to a lower extent in the
olfactory bulb, hypothalamus and thalamus,1 as well as in nocicep-
tive neurons of the dorsal horn. In contrast to most of the ionotro-
pic glutamate receptors, mGlu5 receptors are also widely found in
peripheral tissue,2 for example in peripheral nociceptors or along
the gastric vagal afferents.3 These broad localizations possibly turn
mGlu5 receptors into a drug target for brain disorders as well as for
some peripheral diseases. To date, mGluR5 antagonists have been
sias in Parkinson’s disease (PD-LID),5 migraine6, anxiety7 and
gastro-esophageal reflux disease (GERD).8 Other indications con-
sidered for mGluR5 antagonists include depression,9 chronic pain10
and drug addiction.11
In the course of our mGluR5 drug discovery efforts we found by
scaffold morphing of known mGluR5 antagonists7 that 6-azain-
dole-7-arylcarboxamides (1H-pyrrolo[2,3-c]pyridine-7-arylcarb-
oxamides) constitute an interesting class of potent mGluR5
antagonists, comprising derivatives with nanomolar potency. In
O
O
NH
OH
NH2
O
N
O
N
O
N
N
HN
HN
HN
N
I
II
22
III
60
clinically tested in Fragile X syndrome,4
L-dopa induced dyskine-
Functional test
IC50 (nM):
7
⇑
Corresponding author. Tel.: +41 31 971 58 48.
E-mail address: koller_manuel@bluewin.ch (M. Koller).
Chart 1. Known dipyridyl and benzoxazolone amides with functional data from
literature.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.053

M. Koller et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6454–6459
6455
2
3
NH 1
NH
NH
NH
4
5
O
O
N
O
N
O
N
7
N
N
6
N
N
HN
HN
HN
HN
2'
N
6'
1
2
3
4
Functional test
IC50 (nM):
240
11
3100
13
Chart 2. 6-Azaindole amides as mGluR5 antagonists.
Table 1
Functional data and physico-chemical properties of 6-azaindole-7-carboxamides 1–7
NH
O
R
R5
N
HN
R5
H
R
IC50 (nM)
240
clogPb
logPc
pKa
M.P.e
Solubilityf
a
d
Compound
1
4
N
N
N
2
3
CH3
11 1.7
2.186
4.2
3.5
222
<1
H
3100
8
4
CH3
13 3.8
2.685
5.3
4.5
179
216
<3
N
S
5
6
7
CH3
CH3
CH3
4
1.6
2.548
1.533
1.781
3.9
2.9
3.1
5.6
4.1
7.6
<1
18
52
N
N
670 210
300 21
N
H
N
N
a
Effect on glutamate induced [Ca2+]i in L(tkꢀ)cells expressing human mGluR5a, using a fluorescence imaging plate reader (FLIPR)23; values are means S.E.M. of at least
two independent experiments, or single determinations performed in duplicate.
b
Calculated logP using the clogP program from BioByte (v. 4.71).
Experimental logP.
Experimental pKa of the most basic center.
Melting point (uncorrected) in °C.
c
d
e
f
Equilibrium solubility (mg/l), measured at pH 6.8 using a shake-flask approach.
this letter we would like to report our key findings on this novel
chemotype.
Several years ago Bonnefous et al.12 reported the high potency
of the hydroxy and aminopyridines I and II at rat mGlu5 receptors

6456
M. Koller et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6454–6459
R4
R5
R4
R5
NH
X
NH
R'
NO2
X
i
ii
iii
N
N
N
COOMe
R
X = Br, Cl
R = R' = H
R = CH3, R' = H
R = R' = CH3
R4
R4
R5
NH
iv
NH
R4 = R5 = H:
R4 = H, R5 = CH3: 2; 4 - 7
R4 = R5 = CH3:
1; 3
N
COONa
N
CONHR
9
R5
Scheme 1. General access to the 6-azaindole-7-carboxamides 1–7 and 9. (i) 3 equiv vinylmagnesium bromide, THF, ꢀ78 °C, 90 min (43–47%); (ii) CO (gas) 6 bar (for X@Br) or
55 bar (for X@Cl), MeOH/toluene, NEt3, PdCl2dppfꢁCH2Cl2, 110 °C, 17 h (78–89%); (iii) 1 M NaOH, THF, 25 °C, 1–6 h (90–100%); (iv) RNH2, TBTU, NMM, DMF, 25 °C, 12–24 h
(24–63%).
N
N
Cl
N
i
ii
NO2
Cl
NO2
Cl
NH2
Cl
+
N
N
N
N
N
N
NH
NH
NH
v, vi
iii
iv
O
N
N
Cl
N
COOMe
HN
N
8
Scheme 2. Preparation of 8. (i) PdCl2(PPh3)2, CuI, NEt3, DMF, 100 °C, 90 min (27%); (ii) Fe powder, NH4Cl, EtOH/H2O, 85 °C, 24 h (89%); (iii) CuI, DMF, 110 °C, 60 h, (74%); (iv)
CO (gas) 55 bar, MeOH/toluene, NEt3, PdCl2dppfꢁCH2Cl2, 110 °C, 48 h (74%); (v) 1 M NaOH, THF, 50 °C, 21 h (91%); (vi) 6-methyl-pyridine-2-yl-amine, TBTU, NMM, DMF, 90 °C
(microwave reactor), 1 h (43%).
in a cellular Ca-assay (Chart 1). Soon thereafter Ceccarelli et al.13
described a series of bicyclic bisaryl amides displaying allosteric
negative modulation of mGlu5 receptors, with the benzoxazolone
III as the most potent compound of the examples given. The N-
atom of the five membered ring carries a hydrogen atom in the
same position as the OH-group of compound I and the amino group
of compound II, all three forming an intramolecular hydrogen bond
to the carbonyl group.
Since phenolic OH- and anilinic NH-groups are often causative
for unfavorable pharmacokinetic behavior or toxic metabolism of
a compound, we thought to mask those groups in I and II by incor-
porating them in an annelated pyrrole ring, similar to the situation
in compound III. This concept14 gave rise to the hitherto unknown
6-azaindole carboxamides 1–4 which indeed inhibited glutamate
evoked Ca signals in a cell line transfected with the human mGlu5a
receptor (Chart 2 and Table 1). A binding experiment with the
same cell line using [3H]ABP688 as radioligand15 showed that 4
is a high affinity ligand at the well characterized allosteric binding
site located in the transmembrane region of mGluR516 with a Ki va-
lue of 43 nM.
step i). The halogen atom in position 2 of the pyridine ring allowed
the introduction of a carboxymethyl group in position 7 of the 6-
azaindole scaffold by Pd-catalyzed carbonylation in methanol.18
Saponification of the methyl ester and condensation of the sodium
carboxylate with the appropriate amine provided the 6-azaindole-
7-carboxamides.19
A comparison of the activity of 1 and 2 reveals the crucial role of
the methyl group in position 5 of the azaindole scaffold for high
potency. In contrast, the methyl group in position 60 of the pyridyl
ring is either detrimental (cf. 1 and 3) or, if the 5-methyl group is
installed, does not contribute to potency (cf. 2 and 4). All these
compounds and also the highly potent bioisosteric thiazole analog
5 displayed only marginal aqueous solubility at neutral pH, a con-
sequence of several factors: the compounds are basically nonelec-
trolytes, as the pKa value of the most basic center, the amidic
pyridine or thiazole ring, is in the range of 3.5–5.6; the compounds
are rather lipophilic, as shown by the octanol/water partition coef-
ficient logP which varies from 3.9 to 5.3. Furthermore, the com-
pounds have a pronounced crystallinity,20 as demonstrated by
the high melting points and suggested by their planar conforma-
tions which may strengthen crystal packing.21 The planar confor-
mations are supported by the underestimation of logP by the
The construction of the 6-azaindole scaffold was based on the
Bartoli reaction17 with 3-nitro-pyridine derivatives18 (Scheme 1,

M. Koller et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6454–6459
6457
N
SEM
NH
Br
N
i
ii
iii
SEM
N
N
N
N
N
Br
Ph
Ph
R4 = acetyl: v, vi, vii
R4 = 2-pyridyl: viii, ix
R4
N
N
Br
SEM
SEM
NH
Cl
iv
NH2
R4
N
NH2
R4
N
NH
NH
O
x
xi, xii
N
COOMe
N
HN
R4 = acetyl:
N
10
R4 = 2-pyridyl: 11
Scheme 3. Preparation of the 4-substituted compounds 10 and 11. Preparation of starting material according to Scheme 1; (i) SEMCl, NaH, DMF/DMSO 5:1, 25 °C, 2 h (94%);
(ii) benzhydrylideneamine, Pd(OAc)2, BINAP, Cs2CO3, THF, 70 °C, 50 h (65%); (iii) NH2OHꢁHCl, NaOAc, THF/H2O, 60 °C, 10 min (65%); (iv) PyꢁHBrꢁBr2, CHCl3, 25 °C, 4 h (99%); (v)
1-ethoxyvinyltri-n-butyltin, PdCl2dppfꢁCH2Cl2, dioxane, 120 °C, 22 h (59%); (vi) removal of SEM: HCl concn, ꢀ30 °C 75 min; 2 M NaOH, 75 min (71%); (vii) t-butyl nitrite,
CuCl2, CH3CN, 65 °C, 10 min (7%); (viii) 2-tributylstannanyl-pyridine, PdCl2dppfꢁCH2Cl2, dioxane, 100 °C, 28 h (65%); (ix) NaNO2, HCl concn, 25 °C, 3 h (32%); (x) CO (gas),
55 bar, MeOH/toluene, NEt3, PdCl2dppfꢁCH2Cl2, 110 °C, 72 h (57–62%); (xi) 1 M NaOH, THF, 25 °C, 1 h; (xii) 6-methyl-pyridine-2-yl-amine, TBTU, NMM, DMF, 90 °C, 1 h
(microwave reactor) (56–61% for 2 steps).
R3
R3
Br
vi
viii, ix
vii
NH
NH
NH
NH
R5
N
COOMe
R5
R5
R5
N
I
COOMe
N
CONHR
N
COOMe
N
12 - 15
i, ii
N
N
N
NH
N
N
SO2Ph
iii
SO2Ph iv, v
O
N
N
COOMe
N
COOMe
HN
N
N
16
Scheme 4. Synthesis of the 3-substituted 6-azaindole-7-carboxamides 12–16. Preparation of starting materials according to Scheme 1; (i) NIS, dibenzoylperoxide, CH2Cl2,
25 °C, 1 h (95%); (ii) ClSO2Ph, NaH, DMF, 25 °C, 2 h (42%); (iii) 1-ethyl-2-tributylstannanyl-1H-imidazole (prepared from 1-ethyl-1H-imidazole, n-BuLi, ClSnBu3, THF, ꢀ78 °C),
PdCl2dppf.CH2Cl2, dioxane, 110 °C, 20 h (47%); (iv) 2.1 equiv 1 M NaOH, THF, 50 °C, 3 h (100%); (v) 1-methyl-1H-pyrazol-3-ylamine, TBTU, NMM, DMF, 25 °C, 16 h (54%); (vi)
NBS, dibenzoylperoxide, CH2Cl2, 25 °C, 1 h (65–69%); (vii) R3SnBu3, PdCl2dppf.CH2Cl2, dioxane, 110 °C, 20 h (27–41%); (viii) 1.1 equiv 2 M KOH, THF, 18 h, 50 °C (74–100%);
(ix) RNH2, TBTU, NMM, DMF, 25 °C, 16 h (27–76%).
predicted clogP values, arguing for intramolecular H-bonds be-
tween the NH of the pyrrole ring and the carbonyl group, and be-
tween the amidic NH and N(6) of the azaindole scaffold. Poorly
soluble compounds often lead to absorption problems22 during
pharmaco-kinetic and/or toxicological studies. Therefore we tried
to optimize water solubility while keeping the potency at high le-
vel. As a cutoff for drugability of this chemotype we choose a sol-
ubility at pH 6.8 of 50 mg/l or higher.
Increasing the polarity of the amide substituent by taking 1-
methyl-pyrazol-3-yl or 4-methyl-1H-imidazol-2-yl in place of 2-
pyridyl or 4-methyl-thiazol-2-yl resulted in compounds 6 and 7
which both showed higher solubility but unfortunately much low-
er potency than the pyridyl analogs 2 and 4 (Table 1). The slightly
improved solubility of 6 (vs 5) is likely due to its reduced lipophil-
icity whereas the more marked improvement with 7 can be attrib-
uted to a higher solvation energy, effected by protonation of the
amidic imidazole residue (pKa = 7.6). The structure activity rela-
tionship with respect to the amide group appeared to be rather
steep because no further aromatic five membered ring could be
identified as a replacement of the pyridine or thiazole amide sub-
stituent that was equally well tolerated by the mGlu5 receptor.
The 5-methylated 6-azaindole-7-carboxamide scaffold allows
the attachment of substituents in position 2, 3 and 4, providing
new opportunities for modulation of potency and solubility.
The synthetic approaches used to achieve substitution in these
positions are outlined in Schemes 1–4.19 For compound 8 the Cu-
catalyzed internal cyclization of the appropriate ortho-amino-alky-
nyl pyridine was employed to get the 2-substituted 6-azaindole

6458
M. Koller et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6454–6459
Table 2
Preparation of compounds 10 and 11 made use of protecting
group technology. Protecting the pyrrole N-atom by the 2-(tri-
methylsilyl)ethoxymethyl group (SEM) allowed the regioselective
bromination of the 7-amino-6-azaindole scaffold in para-position
of the amino group (Scheme 3, step iv). For 10 the bromine atom
was replaced in a Stille reaction by the masked acetyl group (step
v). Removal of SEM and Sandmeyer reaction (steps vi, vii) prepared
the intermediate for carbonylation (step x) and subsequent trans-
formation to 10 (steps xi, xii). An analog sequence was used for 11
after execution of the Stille reaction with 2-tributylstannanyl-pyr-
idine (step viii).
Functional data of the 2- and 4-substituted 6-azaindole-7-carboxamides 8–11
R2
R4
NH
O
N
HN
N
Substitution in position 3 (compounds 12 –16) was easily
achieved by iodination or bromination of position 3 of the 6-azain-
dole scaffold (Scheme 4, step i or vi) followed by Pd-catalyzed cou-
pling reaction with the appropriate aryl stannane (step iii or vii).
Compound 8, bearing a 3-pyridyl residue in position 2 and the
60-methyl pyridine as amide substituent, displayed good potency
(Table 2). Its solubility at pH 6.8, however, was still below the limit
of detection. Compounds 9, 10 and 11 with the same amide substi-
tuent and with methyl, acetyl or 2-pyridyl in position 4, respec-
tively, had no improved physico-chemical profile (data not
shown) compared to 4, but were of significantly lower potency (Ta-
ble 2).
a
Compound
R2
R4
H
IC50 (nM)
47 16
8
N
9
10
H
H
CH3
Acetyl
2700 200
540 25
N
11
H
780 35
Position 3 of the 6-azaindole scaffold was explored by a range of
substituents. It was found that decent activity was only obtained
when the heteroatoms of the 3-substituents were placed in well
defined positions. Thus, among the different pyridine regioisomers
the 2-pyridyl substituent, as exemplified in compound 12, turned
out to be the best. As expected, the analog derivative 13, carrying
a
See legend Table 1.
scaffold24 (Scheme 2, step iii). For compound 9, bearing a methyl
group in position 4, the sequence in Scheme 1 could be used, start-
ing from the commercial 2-chloro-5,6-dimethyl-3-nitro-pyridine.
Table 3
Functional data and physico-chemical properties of the 3-substituted 6-azaindole-7-carboxamides 12–16
R3
NH
O
R5
N
HN
R
R3
R5
H
R
IC50 (nM)
clogPb
logPc
pKa
M.P.e
Solubilityf
a
d
Compound
12
540
N
N
N
N
N
13
CH3
31 11
3.303
4.7
4.5
217
<1
14
15
CH3
CH3
CH3
65 11
240 36
54 15
2.152
2.399
2.024
3.7
3.3
2.9
4.6
6.9
7.2
216
222
167
5
N
N
N
H
N
8
N
N
N
16
184
N
N
a–f
See legend Table 1.

M. Koller et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6454–6459
6459
a methyl group in position 5 of the 6-azaindole scaffold, was even
References and notes
more potent. Solubility, however, was still below the limit of detec-
tion, in line with the unfavorable physico-chemical parameters
(Table 3). Changing the amide substituent to 1-methyl pyrazole
or 4-methyl-1H-imidazole (in analogy to 6 and 7, respectively)
gave compounds 14 and 15, both showing slightly improved solu-
bility (Table 3) compared to 13, consistent with the fairly lower
lipophilicity of 14 (logP = 3.7) and the higher pKa of 6.9 for 15.
The finding that an acceptor atom within the 3-substituent is
well tolerated by the receptor if this atom is located beneath the
connection to the azaindole scaffold suggested the possibility for
imidazolyl groups as substituents in position 3. Hence, the combi-
nation of 1-ethyl-imidazol-2-yl in position 3 with 1-methyl-pyra-
zol-3-yl as amide group in 16 resulted in good potency and a
strongly enhanced solubility of 184 mg/l at pH 6.8. Evaluation of
the three aforementioned physico-chemical parameters revealed
drug-like values for 16, with a logP of 2.9, a pKa of 7.2 (correspond-
ing to about 72% of protonation at pH 6.8) and a more moderate
melting point of 167 °C. In an in vitro paradigm using rat liver
microsomes 16 displayed low to medium intrinsic clearance, qual-
ifying the compound for a pharmacokinetic experiment in animals.
To this end, 16 was administered intravenously at 1 mg/kg in rats,
using a cassette model with co-application of five other com-
pounds. Compound 16 was found to have a short plasma half life
of one hour and a moderate to high in vivo clearance of 53 ml/
min/kg which is close to the rat hepatic blood flow of about
56 ml/min/kg.25 Despite an acceptable ratio of brain to blood con-
centration of 0.34 after one hour, the short sojourn in blood disfa-
vored this compound for further investigations. Whether
combinations of substituents in position 2 or 3 of the 6-azaindole
scaffold with appropriate amide groups can be found, conveying
a more favorable pharmacokinetic profile while retaining good po-
tency, remains to be seen.
1. Romano, C.; van den Pol, A. N.; OMalley, K. L. J. Comp. Neurol. 1996, 367, 403.
2. Julio-Pieper, M.; Flor, P. J.; Dinan, T. G.; Cryan, J. F. Pharmacol. Rev. 2011, 63, 35.
3. Rohof, W. O.; Aronica, E.; Beaumont, H.; Troost, D.; Boeckxstaens, G. E.
Neurogastroenterol. Motil. 2012, 24, 383.
4. Gross, C.; Berry-Kravis, E. M.; Bassell, G. J. Neuropsychopharmacol. Rev. 2012, 37,
178.
5. Berg, D.; Godau, J.; Trenkwalder, C.; Eggert, K.; Csoti, I.; Storch, A.; Huber, H.;
Morelli-Canelo, M.; Stamelou, M.; Ries, V.; Wolz, M.; Schneider, C.; Di Paolo, T.;
Gasparini, F.; Hariry, S.; Vandemeulebroecke, M.; Abi-Saab, W.; Cooke, K.;
Johns, D.; Gomez-Mancilla, B. Mov. Disord. 2011, 26, 1243.
6. Keywood, C.; Wakefield, M. Neuropharmacology 2008, 55, 605.
7. Jaeschke, G.; Wettstein, J. G.; Nordquist, R. E.; Spooren, W. Expert Opin. Ther.
Patents 2008, 18, 123.
8. Zerbib, F.; Bruley des Varannes, S.; Roman, S.; Tutuian, R.; Galmiche, J.-P.; Mion,
F.; Tack, J.; Malfertheiner, P.; Keywood, C. Aliment. Pharmacol. Ther. 2011, 33,
911.
9. Palucha, A.; Pilc, A. Pharmacol. Ther. 2007, 115, 116.
10. Montana, M. C.; Gereau, R. W. Curr. Pharmaceutical Biotech. 2011, 12, 1681.
11. Lindsley, C. W.; Bates, B. S.; Menon, U. N.; Jadhav, S. B.; Kane, A. S.; Jones, C. K.;
Rodriguez, A. L.; Conn, P. J.; Olson, C. M.; Winder, D. G.; Emmitte, K. A. ACS
Chem. Neurosci. 2011, 2, 471.
12. Bonnefous, C.; Vernier, J.-M.; Hutchinson, J. H.; Chung, J.; Reyes-Manalo, G.;
Kamenecka, T. Bioorg. Med. Chem. Lett. 2005, 15, 1197.
13. Ceccarelli, S. M.; Jaeschke, G.; Buettelmann, B.; Huwyler, J.; Kolczewski, S.;
Peters, J.-U.; Prinssen, E.; Porter, R.; Spooren, W.; Vieira, E. Bioorg. Med. Chem.
Lett. 2007, 17, 1302.
14. For other examples of phenole/pyrrole bioisosterism see e.g. Leonardi, A.; Riva,
C.; De Toma, C.; Boi, C.; Pennini, R.; Sironi, G. Eur. J. Med. Chem. 1994, 29, 551.
15. Hintermann, S.; Vranesic, I.; Allgeier, H.; Brülisauer, A.; Hoyer, D.; Lemaire, M.;
Moenius, T.; Urwyler, S.; Whitebread, S.; Gasparini, F.; Auberson, Y. P. Bioorg.
Med. Chem. 2007, 15, 903.
16. Pagano, A.; Rüegg, D.; Litschig, S.; Stoehr, N.; Stierlin, C.; Heinrich, M.;
Floersheim, P.; Prezèau, L.; Carroll, F.; Pin, J.-P.; Cambria, A.; Vranesic, I.; Flor, P.
J.; Gasparini, F.; Kuhn, R. J. Biol. Chem. 2000, 275, 33750.
17. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129.
18. Kuehne, H.; Luebbers, T.; Mattei, P.; Maugeais, C.; Pflieger, P.; Scalone, M. U.S.
Patent 185,154, 2007.
19. 1H NMR and UPLC/MS data of the test compounds are reported in
Supplementary data.
20. Jain, N.; Yalkowsky, S. H. J. Pharmaceutical Sci. 2001, 90, 234.
21. Ishikawa, M.; Hashimoto, Y. J. Med. Chem. 2011, 54, 1539.
22. Lipinsky, C. A. J. Pharmacol. Toxicol. Methods 2000, 44, 235.
23. Experimental setup based on Daggett, L. P.; Sacaan, A. I.; Akong, M.; Rao, S. P.;
Hess, S. D.; Liaw, C.; Urrutia, A.; Jachec, C.; Ellis, S. B.; Dreessen, J.; Knöpfel, T.;
Landwehrmeyer, G. B.; Testa, C. M.; Young, A. B.; Varney, M.; Johnson, E. C.;
Veliçelebi, G. Neuropharmacology 1995, 34, 871.
24. Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han, N.; Hurt, R.; Jenkins,
T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.; Santora, V. J.; Sonnenberg, J. D.;
Karbon, W. J. Med. Chem. 2000, 43, 4288.
Acknowledgments
The authors wish to thank A. Bouzan, R. Boesch, V. Cordier, C.
Guibourdenche, M. Gunzenhauser, S. Haessig, J.C. Hengy, M. Reck,
N. Reymann, E. Tasdelen and C. Textor for their excellent technical
assistance.
25. Davies, B.; Morris, T. Pharmaceutical Res. 1993, 1093, 10.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.08.
053.