810
C. Jamieson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 805–811
O
H
O
N
NH2
O
c
a
b
Ph
Br
Br
Br
51
49
50
O
O
H
N
H
e
d
N
O
O
Ph
Ph
O
HO
53
O
52
O
O
H
H
N
N
O
F
F
g
O
F
Ph
F
Ph
f
N
N
F
N
F
N
O
OH
55
54
O
F
R
H
N
S
NH2
O
F
O
F
h
F
N
N
F
N
F
N
24 - 28
OH
OH
56
Scheme 6. Reagents and conditions: (a) (i) NH2OHꢁHCl, EtOH, reflux; (ii) Zn, AcOH, rt 68% (over two steps); (b) benzyl chloroformate, K2CO3, EtOAc/water; 67%; (c) acetoxy-
(2-(dio-tolylphosphino)benzyl)palladium, PtBu3ꢁHBF4, DBU, MeCN/MeOH, 150 °C,
lW, 77%; (d) LiAlH4, THF, rt, 48%; (e) (i) SOCl2, CH2Cl2, rt; (ii) ethyl (3-(trifluoromethyl)-1H-
pyrazolyl-4-yl)carboxylate, K2CO3, 60 °C, 84% (over two steps); (f) LiAlH4, THF, rt, 74%; (g) Pd(OH)2, EtOH/5 N HCl, H2 (2 bar), 83%; (h) sulfonyl chloride RSO2Cl, Et3N, CH2Cl2,
24–32%.
Compounds 7–11 were prepared as outlined in Scheme 3. Bro-
mination of 2-aminoindane followed by resolution16 gave enantio-
merically pure amine 38.
valuable tool in further understanding the potential role of AMPA
receptor modulators in complex neurological disorders.
Sulfonylation followed by palladium mediated carbonylation
and reduction gave alcohol 41 which could then be chlorinated
and used to alkylate the appropriate azole derivative. Compound
8 was obtained directly from 7 by treatment with DAST, while
compound 13 could be obtained via careful chromatographic sep-
aration from 7.
Scheme 4 outlines the preparation of analogues 14 and 16. The
boronate ester 43 was prepared and used in a palladium catalysed
sp2–sp3 coupling17 to furnish both target compounds.
Sulfonamide derivatives 17–23 were prepared according to the
synthetic plan delineated in Scheme 5. Resolution of aminoindane
37 with either L- or D-CSA gave (S) or (R) enantiomers, respec-
tively. Cbz protection followed by carbonylation and subsequent
reduction gave 46a/46b as separate compounds, both of which
could be converted to the chloride derivative and used to alkylate
the requisite pyrazole alcohol. Protecting group removal followed
by the final diversity step gave target compounds 17–23 as discrete
enantiomers.
Compounds 24–28 were prepared in an analogous fashion to
the above starting from 5-bromo-2,3-dihydro-1H-inden-amine
(50) which is prepared via reduction of an oxime intermediate de-
rived from 5-bromoindan-1-one (49, Scheme 6).
References and notes
1. Kew, J. N. C.; Kemp, J. A. Psychopharmacology 2005, 179, 4.
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J.; Kazemier, B.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; Maclean, J. K. F.; Moir, E. M.;
Morrow, J. A.; Papakosta, M.; Rankovic, Z.; Smith, L. Bioorg. Med. Chem. Lett.
2010, 20, 5753.
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B.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; Maclean, J. K. F.; Martin, F.; Moir, E. M.;
Morrow, J. A.; Pantling, J.; Rankovic, Z.; Smith, L. Bioorg. Med. Chem. Lett. 2010,
20, 6072.
6. Armstrong, N.; Sun, Y.; Chen, G. Q.; Gouaux, E. Nature 1998, 395, 913.
7. HEKꢁGluR1(i) cells were maintained in DMEM supplemented with 10%
fetaclone II, 1% non-essential amino acids and 150 lg/mL hygromycin, at
37 °C/5% CO2. Twenty-four hour prior to the assay, the cells were harvested
with trypsin and seeded onto Costar 96-well clear bottomed black plates at a
density of 3.5 ꢂ 104 per well. Cells were loaded with 5
lM fluo3-AM in DMEM
media in the absence of hygromycin and incubated at 37 °C/5% CO2 for 1 h.
After dye loading, the cells were washed once with 200 ll of low calcium
solution (10 mM hepes, pH 7.4, 160 mM NaCl, 4.5 mM KCl, 2 mM CaCl2, 1 mM
MgCl2, 10 mM glucose) containing 0.625 mM of probenecid to remove the dye.
Then 200
added 50
ll of low calcium solution was added to each well. The FLEXstation
ll of glutamate +/ꢀ test compound in high calcium solution (10 mM
Hepes, pH 7.4, 160 mM NaCl, 4.5 mM KCl, 20 mM CaCl2, 1 mM MgCl2 and
10 mM glucose) to each well and the ensuing response was monitored on
FLEXstation.
8. Quirk, J. C.; Nisenbaum, E. CNS Drug Rev. 2002, 8, 255.
In summary, a critical component of our scaffold hopping strat-
egy has been the application of structure-based drug design
(SBDD) against an ion channel target, both directing our template
modifications and offering key insights into SAR within the series.
Starting from lead compound 1, we have demonstrated optimiza-
tion to yield a structurally differentiated entity (19) with an
excellent overall balance of properties. We believe 19 will be a
9. Sobolevsky, A. I.; Rosconi, M. P.; Gouaux, E. Nature 2009, 462, 745.
10. Ward, S. E.; Harries, M.; Aldegheri, L.; Andreotti, D.; Ballantine, S.; Bax, B. D.;
Harries, A. J.; Harker, A. J.; Lund, J.; Melarange, R.; Mingardi, A.; Mookherjee, C.;
Mosley, J.; Neve, M.; Oliosi, B.; Profeta, R.; Smith, K. J.; Smith, P. W.; Spada, S.;
Thewlis, K. M.; Yusaf, S. P. J. Med. Chem. 2010, 53, 5801.
11. Crystals were grown as described in Ref..4 Co-crystallizations were performed
by soaking apo crystals in 100 mM test compound for 24 h prior to data
collection. Coordinates and structure factors have been deposited with the