Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 1, 2010, Pages 184-188

  Spanka, Carsten ^a   Glatthar, Ralf ^a   Desrayaud, Sandrine ^a   Fendt, Markus ^a   Orain, David ^a   Troxler, Thomas ^a   Vranesic, Ivo ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Metabotropic glutamate receptor; mGluR5 antagonist; Piperidylamides

Indexed keywords

2 ETHYLPIPERIDINEAMIDE; 2,2' DIPYRIDYLAMINE DERIVATIVE; ANXIOLYTIC AGENT; BENZAMIDE; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR ANTAGONIST; NICOTINAMIDE DERIVATIVE; PIPERIDYLAMIDE DERIVATIVE; PYRAZINAMIDE; PYRAZOLE 3 CARBOXAMIDE; PYRIDAZINE DERIVATIVE; PYRIMIDINE 5 CARBOXAMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANXIETY; ARTICLE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG EFFECT; DRUG STRUCTURE; DRUG SYNTHESIS; FEAR; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HYPERTHERMIA; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TRANQUILIZING ACTIVITY;

ADMINISTRATION, ORAL; AMIDES; AMINOPYRIDINES; ANIMALS; ANTI-ANXIETY AGENTS; HUMANS; MICROSOMES, LIVER; PEPTIDES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA; RATTUS;

EID: 72149100751     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.11.001     Document Type: Article

References (38)

1. Swanson C.J., Bures M., Johnson M.P., Linden A.-M., Monn J.A., and Schoepp D.D. Nat. Rev. Drug Disc. 4 (2005) 131
2. Ritzen A., Mathiesen J.M., and Thomsen C. Basic Clin. Pharmacol. Toxicol. 97 (2005) 202
3. Knöpfel T., Kuhn R., and Allgeier H. J. Med. Chem. 38 (1995) 1417
4. Conn P.J., and Pin J.P. Annu. Rev. Pharmacol. Toxicol. 37 (1997) 205
5. Shigemoto R., Nomura S., Ohishi H., Sugihara H., Nakanishi S., and Mizuno N. Neurosci. Lett. 163 (1993) 53
6. Romano C., Sesma M.A., McDonald C.T., O'Malley K., Van den Pol A.N., and Olney J.W. J. Comp. Neurol. 355 (1995) 455
7. Rodrigues S.M., Bauer E.P., Farb C.R., Schafe G.E., and LeDoux J.E. J. Neurosci. 22 (2002) 5219
8. Phan K.L., Fitzgerald D.A., Cortese B.M., Seraji-Bozorgzad N., Tancer M.E., and Moore G.J. NeuroReport 16 (2005) 183
9. Mathew S.J., Price R.B., and Charney D.S. Am. J. Med. Genet. C Semin. Med. Genet. 148 (2008) 89
10. Bradbury M.J., Campbell U., Giracello D., Chapman D., King C., Tehrani L., Cosford N.D.P., Anderson J., Varney M.A., and Strack A.M. J. Pharmacol. Exp. Ther. 313 (2005) 395
11. Breysse N., Baunez C., Spooren W., Gasparini F., and Amalric M. J. Neurosci. 22 (2002) 5669
12. Zhu C.Z., Wilson S.G., Mikusa J.P., Wismer C.T., Gauvin D.M., Lynch III J.L., Wade C.L., Decker M.W., and Honore P. Eur. J. Pharmacol. 506 (2004) 107
13. Mutel V. Expert Opin. Ther. Pat. 12 (2002) 1845
14. Chiamulera C., Epping-Jordan M.P., Zocchi A., Marcon C., Cottiny C., Tacconi S., Corsi M., Orzi F., and Conquet F. Nat. Neurosci. 4 (2001) 873
15. Gasparini F., Lingenhöhl K., Stoehr N., Flor P.J., Heinrich M., Vranesic I., Biollaz M., Allgeier H., Heckendorn R., Urwyler S., Verney M.A., Johnson E.C., Hess S.D., Rao S.P., Sacaan A.I., Santori E.M., Velicelebi G., and Kuhn R. Neuropharmacology 38 (1999) 1493
16. Spooren W.P.J.M., Vassout A., Neijt H.C., Kuhn R., Gasparini F., Roux S., Porsolt R.D., and Gentsch C. Pharmacol. Exp. Ther. 295 (2000) 1267
17. Schulz B., Fendt M., Gasparini F., Lingenhöhl K., Kuhn R., and Koch M. Neuropharmacology 41 (2001) 1
18. Daggett L.P., Sacaan A.I., Akong M., Rao S.P., Hess S.D., Liaw C., Urrutia A., Jachec C., and Ellis S.B. Neuropharmacology 34 (1995) 871
19. Flor P.J., Gomeza J., Tones M.A., Kuhn R., Pin J.-P., and Knoepfel T. J. Neurochem. 67 (1996) 58
20. Knopfel T., Sakaki J., Flor P.J., Baumann P., Sacaan A.I., Velicelebi G., Kuhn R., and Allgeier H. Eur. J. Pharmacol. 288 (1994) 389
21. Kamenecka T.M., Bonnefous C., Govek S., Vernier J.-M., Hutchinson J., Chung J., Reyes-Manalo G., and Anderson J.J. Bioorg. Med. Chem. Lett. 15 (2005) 4350
22. 6-Chloro-5-methoxynicotinic acid required for the preparation of 13c was prepared in analogy to Stump, C. A.; Williams, T. M. PCT International Patent Application WO 00/51614, example 4.
23. 5-(4-Chloro-phenylamino)-2H-pyrazole-3-carboxylic acid required for the synthesis of 13i was prepared in analogy to a procedure published by. Radl S. Coll. Czech. Chem. Commun. 57 (1992) 656
24. Hintermann S., Vranesic I., Allgeier H., Bruelisauer A., Hoyer D., Lemaire M., Moenius T., Urwyler S., Whitebread S., Gasparini F., and Auberson Y.P. Bioorg. Med. Chem. 15 (2007) 903
25. Pagano A., Ruegg D., Litschig S., Stoehr N., Stierlin C., Heinrich M., Floersheim P., Prezeau L., Carroll F., Pin J.P., Cambria A., Vranesic I., Flor P.J., Gasparini F., and Kuhn R. J. Biol. Chem. 275 (2000) 33750
26. i: 30 nM) was observed in membranes prepared from cells expressing rat brain tissue (cortex/hippocampus).
27. Selectivity to ionotropic glutamate receptors was assessed with radioligand displacement assays in rat brain membranes at the AMPA (glutamate binding site), kainate (glutamate binding site) and NMDA (glutamate and glycine binding sites) subtypes.
28. Spooren W.P.J.M., Gasparini F., Salt T.E., and Kuhn R. Trends Pharmacol. Sci. 22 (2001) 331
29. Adriaan Bouwknecht J., Olivier B., and Paylor R.E. Neurosci. Biobehav. Rev. 31 (2007) 41
30. Vogel J.R., Beer B., and Clody D.E. Psychopharmacology 21 (1971) 1
31. Millan M.J., and Brocco M. Eur. J. Pharm. 463 (2003) 67
32. Brown J.S., Kalish H.I., and Farber I.E. J. Exp. Psychol. 41 (1951) 317
33. Davis M. Behav. Neurosci. 100 (1986) 814
34. Davis M., Falls W.A., and Campeau S. Behav. Brain Res. 58 (1993) 175
35. Fendt M., and Fanselow M.S. Neurosci. Biobehav. Rev. 23 (1999) 743
36. Koch M. Prog. Neurobiol. 59 (1999) 107
37. Davis M. Biol. Psychiat. 44 (1998) 1239
38. Grillon C., and Davis M. Psychophysiology 34 (1997) 451