The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA α5 inverse agonists for the treatment of cognitive dysfunction

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 20, 2009, Pages 5940-5944

  Knust, Henner ^a   Achermann, Guido ^a   Ballard, Theresa ^a   Buettelmann, Bernd ^a   Gasser, Rodolfo ^a   Fischer, Holger ^a   Hernandez, Maria Clemencia ^a   Knoflach, Frédéric ^a   Koblet, Andreas ^a   Stadler, Heinz ^a   Thomas, Andrew W ^a   Trube, Gerhard ^a   Waldmeier, Pius ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Clinical candidate; GABAA receptor subtypes; Lead optimisation; Neuroscience

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA5; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; RO 4882224; RO 4938581; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COGNITIVE DEFECT; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; DRUG SCREENING; DRUG SOLUBILITY; DRUG STRUCTURE; HUMAN; HUMAN CELL; LEARNING DISORDER; MEMORY DISORDER; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTICONVULSANTS; BENZODIAZEPINES; CELL LINE; COGNITION DISORDERS; DISEASE MODELS, ANIMAL; DRUG DISCOVERY; DRUG INVERSE AGONISM; HUMANS; IMIDAZOLES; MICE; PROTEIN BINDING; RATS; RECEPTORS, GABA-A; SEIZURES; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 70349192800     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.053     Document Type: Article

References (24)

1. Haefely W.E. Eur. Arch. Psychiatry Neurol. Sci. 238 (1989) 294
2. Dawson G.R., Maubach K.A., Collinson N., Cobain M., Everitt B.J., MacLeod A.M., Choudhury H.I., McDonald L.M., Pillai G., Rycroft W., Smith A.J., Sternfeld F., Tattersall F.D., Wafford K.A., Reynolds D.S., Seabrook G.R., and Atack J.R. J. Pharmacol. Exp. Ther. 3163 (2006) 1335
3. Maubach K. Curr. Drug Targets CNS Neurol. Disorders 2 (2003) 233
4. Maubach K.A. Drugs Future 31 (2006) 151 and references cited within
5. Rissmann R.A., De Blas A.L., and Armstrong D.M. J. Neurochem. 103 (2007) 1285
6. Möhler H., Rudolph U., Boison D., Singer P., Feldon J., and Yee B.K. Pharmacol., Biochem. Behav. 90 (2008) 58
7. Möhler H., and Rudolph U. Drug Disc. Today: Ther. Strategies 1 (2004) 117
8. Birks, J.; Harvey, R. J. Cochrane Database Syst. Rev. 2006, CD001190.
9. McShane, R.; Areosa Sastre, A.; Minakaran, N. Cochrane Database Syst. Rev. 2006, CD003154.
10. 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., and Wichmann J. Bioorg. Med. Chem. Lett. 19 (2009) 5746
11. Knust, H.; Stadler, H.; Thomas, A. W. U.S. Patent 20060079507A1: Chem. Abstr. 2006, 144, 370129
12. Knust, H.; Thomas, A. W. U.S. Patent 20060084642A1: Chem. Abstr. 2006, 144, 390949
13. Knust, H.; Thomas, A. W. U.S. Patent 20060084801A1: Chem. Abstr. 2006, 144, 412549
14. Büttelmann, B.; Knust, H.; Thomas, A. W. U.S. Patent 2006128691A1: Chem. Abstr. 2006, 145, 46099.
15. Roche D., Prasad K., Repic O., and Blacklock T.J. Tetrahedron Lett. 41 (2000) 2083
16. Gerecke M., Kyburz E., Borer R., and Gassner W. Heterocycles 39 (1994) 693
17. 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.
18. 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.
19. Gonzalez R.C.B., Huwyler J., Boess F., Walter I., and Bittner B. Biopharm. Drug Dispos. 25 (2004) 37
20. Kansy M., Fischer H., Kratzat K., Senner F., Wagner B., and Parrilla I. Helv. Chim. Acta (2000) 447
21. Seabrook G.R., Dawson G.R., Easter A., and Bowery B.J. Neuropharmacology 36 (1997) 823
22. 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., and Hernandez M.-C. Psychopharmacology 202 (2009) 207
23. Higgins G.A., Enderlin M., Fimbel R., Haman M., Grottick A.J., Soriano M., Richards J.G., Kemp J.A., and Gill R. Eur. J. Neurosci. 15 (2002) 1827
24. For the effect of the functionally selective compound α5IA-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.