Development and SAR of functionally selective allosteric modulators of GABAA receptors

Bioorganic and Medicinal Chemistry

Volumn 19, Issue 9, 2011, Pages 2927-2938

  Alhambra, Cristobal ^a   Becker, Chris ^a   Blake, Timothy ^a   Chang, Amy ^a   Damewood Jr , James R ^a   Daniels, Thalia ^a   Dembofsky, Bruce T ^a   Gurley, David A ^a   Hall, James E ^a   Herzog, Keith J ^a   Horchler, Carey L ^a   Ohnmacht, Cyrus J ^a   Schmiesing, Richard Jon ^a   Dudley, Adam ^a   Ribadeneira, Maria D ^a   Knappenberger, Katherine S ^a   MacIag, Carla ^a   Stein, Mark M ^a   Chopra, Maninder ^a   Liu, Xiaodong F ^a   Christian, Edward P ^a   Arriza, Jeffrey L ^a   Chapdelaine, Marc J ^a   more..

^a ASTRAZENECA   (United Kingdom)

Author keywords

Allosteric modulator; Anxiety; Benzodiazepine; Cinnoline; GABAA receptor; Quinoline; Subtype functional selectivity

Indexed keywords

2 AMINO 3 BROMO 4 FLUORO BENZONITRILE; 2 AMINO 3 BROMOBENZONITRILE; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA1; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA2; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA3; 4 METHOXY 1 (ALKYL) 1,5 DIHYDROPYRROL 2 ONE; CINNOLINE DERIVATIVE; N (ALKYL) 2 CYANOACETAMIDE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; UNCLASSIFIED DRUG;

ALLOSTERISM; ANXIETY; ARTICLE; BINDING ASSAY; BINDING SITE; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OOCYTE; STRUCTURE ACTIVITY RELATION; VOLTAGE CLAMP;

ALLOSTERIC REGULATION; ANTI-ANXIETY AGENTS; BENZODIAZEPINES; GABA-A RECEPTOR ANTAGONISTS; HETEROCYCLIC COMPOUNDS, 2-RING; QUINOLINES; RECEPTORS, GABA-A; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79955415674     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2011.03.035     Document Type: Article

References (27)

1. Campbell, J. B.; Warawa, E. J. European Patent Application 87303949.9, 1987.
2. Patel, J. B.; Meiners, B. A.; Salama, A. I.; Malick, J. B.; Resch, J. F.; U'Pritchard, D. C.; Giles, R. E.; Hesp, B.; Goldberg, M. E. Prog. Clin. Biol. Res. 1990, 361 (Curr. Future Trends Anticonvulsant, Anxiety, Stroke Ther.), 483.
3. Resch, J. F. Ger. (East) Patent DD 249011, 1987.
4. Resch, J. F. European Patent Application 89300865.6, 1989.
5. W. Sieghart, K. Fuchs, V. Tretter, V. Ebert, M. Jechlinger, H. Hoger, and D. Adamiker Neurochem. Int. 34 1999 379
6. E.R. Korpi, M.J. Matilla, W. Wisden, and H. Luddens Ann. Med. 29 1997 275
7. J.R. Atack Curr. Drug Targets CNS Neurol. Disord. 2 2003 213
8. R.M. McKernan, T.W. Rosahl, D.S. Reynolds, C. Sur, K.A. Wafford, J.R. Atack, S. Farrar, J. Myers, G. Cook, P. Ferris, L. Garrett, L. Bristow, G. Marshall, A. Maccaulay, N. Brown, K.W. Moore, R.W. Carling, L.J. Street, J.L. Castro, C.I. Ragan, G.R. Dawson, and P.J. Whiting Nat. Neurosci. 3 2000 587
9. K. Low, F. Crestani, R. Keist, D. Benke, I. Brunig, J.A. Benson, J.-M. Fritschy, T. Rulicke, H. Bluethman, H. Mohler, and U. Rudolph Science 290 2000 131
10. J.R. Atack Expert Opin. Invest. Drugs 14 2005 601
11. A modulator such as TPA023 and other selective modulators to be anxiolytic see: J.R. Atack Adv. Pharmacol. 57 2009 137 and references cited therein
12. Chapdelaine, M. J.; Ohnmacht, C. J.; Becker, C.; Chang, H.-F.; Dembofsky, B. T. US Patent 2007/0142328 A1.
13. Alhambra, C.; Chang, H.-F.; Chapdelaine, M.; Herzog, K. J.; Schmiesing, R. J. WO Patent 2011/021979 A1.
14. Chang, H.-F.; Chapdelaine, M. J.; Dembofsky, B. T.; Herzog, K. J.; Horchler, C.; Schmiesing, R. J. WO Patent 2008/155572 A2.
15. For general reviews on bioisosteres in medicinal chemistry see: C.W. Thornber Chem. Soc. Rev. 8 1979 563
16. P.H. Olesen Curr. Opin. Drug Disc. Dev. 4 2001 471
17. G.A. Patani, and E.J. LaVoie Chem. Rev. 96 1996 3147
18. For a discussion of matched pair analysis and the effect of a structural change on physical properties see: A.G. Leach, H.D. Jones, D.A. Cosgrove, P.W. Kenny, L. Ruston, P. MacFaul, J.M. Wood, N. Colclough, and B. Law J. Med. Chem. 49 2006 6672
19. Christian, E. P.; Snyder, D. H.; Song, W.; Gurley, D. A.; Quirk, M. C.; Smolka, J.; McLaughlin, J.; Maier, D. L.; Ding, M. Gharahdaghi, F.; Liu, X. F.; Chopra, M.; Ribadeneria, M.; Chapdelaine, M. J.; Dudley, A.; Arriza, J.; Maciag, C.; Doherty, J. J. Neuropsychopharmacology, submitted for publication.
20. The desired values in Table 1 were used as a first filter for ranking compounds for further in vitro characterization; they evolved as the project progressed.
21. Where standard deviations are included, the results reflect a minimum of three replicates. See Section 4.3.1 for a description of the assay.
22. Where standard deviations are included, the results reflect a minimum of three replicates. See Section 4.3.2 for a description of the assay.
23. The results reflect a minimun of three replicates. See Section 4.3.3 for a description of the assay.
24. The results reflect a minimun of three replicates. See Section 4.3.4 for a description of the assay.
25. A receptors'" X.F. Liu, H.-F. Chang, R.J. Schmiesing, S.S. Wesolowski, K.S. Knappenberger, J.L. Arriza, and M.J. Chapdelaine Bioorg. Med. Chem. 18 2010 8374
26. Lappalainen, Jaakko, personal communication
27. www.clinicaltrials.gov.