5
944
H. Knust et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5940–5944
Sternfeld, F.; Tattersall, F. D.; Wafford, K. A.; Reynolds, D. S.; Seabrook, G. R.;
N
N
N
Cl
CHF2
Atack, J. R. J. Pharmacol. Exp. Ther. 2006, 3163, 1335.
N
N
N
N
3.
(a) Maubach, K. Curr. Drug Targets CNS Neurol. Disorders 2003, 2, 233; (b)
Maubach, K. A. Drugs Future 2006, 31, 151. and references cited within; (c)
Rissmann, R. A.; De Blas, A. L.; Armstrong, D. M. J. Neurochem. 2007, 103, 1285;
Cl
Br
N
N
N
(
d) Möhler, H.; Rudolph, U.; Boison, D.; Singer, P.; Feldon, J.; Yee, B. K.
Pharmacol., Biochem. Behav. 2008, 90, 58; (e) Möhler, H.; Rudolph, U. Drug Disc.
Today: Ther. Strategies 2004, 1, 117.
1
1
44
4
5
.
.
Birks, J.; Harvey, R. J. Cochrane Database Syst. Rev. 2006, CD001190.
McShane, R.; Areosa Sastre, A.; Minakaran, N. Cochrane Database Syst. Rev.
Scheme 3. Clinical candidates RO4882224 (11) and RO4938581 (44).
2006, CD003154.
6.
Achermann, A.; Ballard, T.; Blasco, F.; Broutin, P.-E.; Büttelmann, B.; Fischer, H.;
Graf, M.; Hernandez, M.-C.; Hilty, P.; Knoflach, F.; Koblet, A.; Knust, H.; Kurt, A.;
Martin, J. R.; Masciadri, R.; Porter, R. H. P.; Stadler, H.; Thomas, A. W.; Trube, G.;
Wichmann, J. Bioorg. Med. Chem. Lett. 2009, 19, 5746.
(
2
p <0.01) reversed the scopolamine-induced impairment at 16 and
4 s delay intervals (Fig. 1b).17
7
.
(a) Knust, H.; Stadler, H.; Thomas, A. W. U.S. Patent 20060079507A1: Chem.
Abstr. 2006, 144, 370129; (b) Knust, H.; Thomas, A. W. U.S. Patent
20060084642A1: Chem. Abstr. 2006, 144, 390949; (c) Knust, H.; Thomas, A.
W. U.S. Patent 20060084801A1: Chem. Abstr. 2006, 144, 412549; (d)
Büttelmann, B.; Knust, H.; Thomas, A. W. U.S. Patent 2006128691A1: Chem.
Abstr. 2006, 145, 46099.
Roche, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2000, 41,
2083.
Gerecke, M.; Kyburz, E.; Borer, R.; Gassner, W. Heterocycles 1994, 39, 693.
Supported by these results the imidazo[1,5-a][1,2,4]-triazol-
o[1,5-d][1,4]benzodiazepines 11 and 44 have been selected as clin-
ical candidates for further development (Scheme 3).
An ambitious lead optimisation programme delivered, by
extensive structure–activity- and structure–efficacy-relationship
work, within the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzo-
8
.
.
9
diazepine chemical class, potent inverse agonists at the GABA
5 receptor sub type, which feature both binding and functional
A
1
1
0. Standard activation as iminoyl-chloride resulted in low yield reactions due to
instability during the necessary aqueous work-up. The corresponding iminoyl-
triazolide was in contrast stable and convenient to handle.
a
selectivity in a unique pharmacological profile. This dual binding
and functional selectivity offers an ideal profile for cognition-
enhancing effects without the unwanted side effects associated
1. Different reduction sequences led to the alkyl-substituted products (optionally
fluorinated) while
a decarboxylation process afforded the unsubstituted
products which could further be derivatised, for example, by halogenation.
with activity at other GABA
in vivo DMTP data further support the potential of GABA
receptors as a valuable target for cognition-enhancing therapies.
A
receptor subtypes. Furthermore, the
12. Gonzalez, R. C. B.; Huwyler, J.; Boess, F.; Walter, I.; Bittner, B. Biopharm. Drug
Dispos. 2004, 25, 37.
A
a5
1
1
1
3. Kansy, M.; Fischer, H.; Kratzat, K.; Senner, F.; Wagner, B.; Parrilla, I. Helv. Chim.
Acta 2000, 447.
4. Seabrook, G. R.; Dawson, G. R.; Easter, A.; Bowery, B. J. Neuropharmacology
1997, 36, 823.
Acknowledgements
5. Ballard, T. M.; Knoflach, F.; Prinssen, E.; Borroni, E.; Vivian, J. A.; Basile, J.;
Gasser, R.; Moreau, J.-L.; Wettstein, J. G.; Büttelmann, B.; Knust, H.; Thomas, A.
W.; Trube, G.; Hernandez, M.-C. Psychopharmacology 2009, 202, 207.
Special thanks to Anton Cueni, Béatrice David, Michel Enderlin,
Cécile Guiziani, Rachel Haab, Marie-Laurence Harle-Yge, Maria
Karg, Marie Claire Pflimlin, Pascal Pflimlim, Claudio Plozza, Regina
Wolf for technical excellence in their work and to Alex Alanine for
proofreading of this manuscript.
16. Higgins, G. A.; Enderlin, M.; Fimbel, R.; Haman, M.; Grottick, A. J.; Soriano, M.;
Richards, J. G.; Kemp, J. A.; Gill, R. Eur. J. Neurosci. 2002, 15, 1827.
17. For the effect of the functionally selective compound a5IA-II (Collinson, N.;
Atack, J. R.; Laughton, P.; Dawson, G. R.; Stephens, D. N. Psychopharmacology,
2006, 188, 619 and Sternfeld, F.; Carling, R. W.; Jelley, R. A.; Ladduwahetty, T.;
Merchant, K. J.; Moore, K. W.; Reeve, A. J.; Street, L. J.; O’Connor, D.; Sohal, B.;
Atack, J. R.; Cook, S.; Seabrook, G.; Wafford, K.; Tattersall, F. D.; Collinson, N.;
Dawson, G. R.; Castro, J. L., MacLeod, A. M. J. Med. Chem. 2004, 47, 2176.) as a
control substance in this cognition task see: Buettelmann B.; Ballard T. M.;
Gasser R.; Fischer H.; Hernandez M.-C.; Knoflach F.; Knust H.; Stadler H.;
Thomas A. W.; Trube G. Bioorg. Med. Chem. Lett. 2009, 19, 5958.
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