Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2- ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist

Journal of Medicinal Chemistry

Volumn 50, Issue 4, 2007, Pages 807-819

  Liverton, Nigel J ^a   Bednar, Rodney A ^a   Bednar, Bohumil ^a   Butcher, John W ^a   Claiborne, Christopher F ^a   Claremon, David A ^a   Cunninghan, Michael ^a   DiLella, Anthony G ^a   Gaul, Stanley L ^a   Libby, Brian E ^a   Lyie, Elizabeth A ^a   Lynch, Joseph J ^a   McCauley, John A ^a   Mosser, Scott D ^a   Nguyen, Kevin T ^a   Stump, Gary L ^a   Sun, Hong ^a   Wang, Hao ^a   Yergey, James ^a   Koblan, Kenneth S ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 BENZYL ALPHA (4 HYDROXYPHENYL) BETA METHYL 1 PIPERIDINEPROPANOL; 4 METHYLBENZYL 4 [(2 PYRIMIDINYLAMINO)METHYL] 1 PIPERIDINECARBOXYLATE; AMINOPYRIDINE DERIVATIVE; BENZYL 4 [(PYRIDIN 4 YLAMINO)METHYL]PIPERIDINE 1 CARBOXYLATE; CARBAMIC ACID DERIVATIVE; CI 1041; DIZOCILPINE; IFENPRODIL; KETAMINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2B; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; PIPERIDINE DERIVATIVE; POTASSIUM CHANNEL HERG; TRAXOPRODIL; UNCLASSIFIED DRUG;

ALLODYNIA; ANIMAL EXPERIMENT; ANTINOCICEPTION; ARTICLE; BRAIN; CHEMICAL REACTION; CONTROLLED STUDY; DOG; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; EX VIVO STUDY; EXPERIMENTAL MODEL; FEMALE; HIGH THROUGHPUT SCREENING; MALE; NONHUMAN; PARKINSON DISEASE; RAT; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANALGESICS; ANIMALS; ANTIPARKINSON AGENTS; BIOLOGICAL AVAILABILITY; BRAIN; CELL LINE; DOGS; FEMALE; FRONTAL LOBE; HUMANS; MALE; PAIN MEASUREMENT; PYRIMIDINES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, N-METHYL-D-ASPARTATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33847401357     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060983w     Document Type: Article

References (43)

1. Michaelis, E. K. Molecular Biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 1998, 54, 369-415.
2. Carling, R. W.; Leeson, P. D.; Moore, K. W.; Moyes, C. R.; Duncton, M.; Hudson, M. L.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. 4-Substituted-3-phenylquinolin-2(1H)- ones: acidic and nonacidic glycine site N-methyl-D-aspartate antagonists with in vivo activity. J. Med. Chem. 1997, 40, 754-765.
3. Parsons, C. G.; Danysz, W.; Quack, G. Glutanate in CNS disorders as a target for drug development: an update. Drug News Perspect. 1998, 11, 523-569.
4. Eide, P. K.; Stubhaug, A.; Øye, I.; Breivik, H. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995, 61, 221-228.
5. Eide, P. K.; Jørum, E.; Stubhaug, A.; Bremnes, J.; Breivk, H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994, 58, 347-354.
6. Chizh, B. A.; Headley, P. M. NMDA antagonists and neuropathic pain - multiple drug targets and multiple uses. Curr. Pharm. Design 2005, 11, 2977-2994.
7. Kingery, W. S. A critical review of controlled clinical trials for peripheral and neuropathic pain and complex regional pain syndromes. Pain 1997, 73, 123-139.
8. Cull-Candy, S.; Brickley, S.; Farrant, M. NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 2001, 11, 327-335.
9. McBain, C. J.; Mayer, M. L. N-Methyl-D-aspartate receptor structure and function. Phys. Rev. 1994, 74, 723-760.
10. Boyce, S.; Wyatt A.; Webb, J. K.; O'Donnell, R.; Mason, G.; Rigby, M.; Sirinathsinghji, D.; Hill, R. G.; Rupniak, N. M. J. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology 1999, 38, 611-623.
11. Wei, F.; Wang, G.-D.; Kerchner, G. A.; Kim, S. J.; Xu, H.-M.; Chen, Z.-F.; Zhuo, M Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat. Neurosci. 2001, 4, 164-9.
12. Williams, K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 1993, 44, 851-859.
13. Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J. N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A. Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J. Pharm. Exp. Ther. 1997, 283, 1285-1292.
14. Chenard, B. L.; Bordner, J.; Butler, T. W.; Chambers, L. K.; Collins, M. A.; De Costa, D. L.; Ducat, M. F.; Dumont, M. L.; Fox, C. B.; Mena, E. E.; Menniti, F. S.; Nielsen, J.; Pagnozzi, M. J.; Richter, K. E. G.; Ronau, R. T.; Shalaby, I. A.; Stemple, J. Z.; White, W. F. (1S,2S)-1-(4-Hydroxyphenyl)-2-(4- hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J. Med. Chem. 1995, 38, 3138-3145.
15. Barton, M. E.; White, H. S. The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. Epilepsy Res. 2004, 59, 1-12.
16. For recent reviews, see: McCauley, J. A. NR2B subtype-selective NMDA receptor antagonists: 2001-2004. Expert Opin. Ther. Pat. 2005, 15, 389-407.
17. Borza, I.; Domány, D. NR2B Selective NMDA antagonists: the evolution of the ifenprodil-type pharmacophore. Curr. Top. Med. Chem. 2006, 6, 687-695.
18. Layton, M. E.; Kelly, M. J.; Rodzinak, K. J. Recent advances in the development of NR2B subtype-selective NMDA receptor antagonists. Curr. Top. Med. Chem. 2006, 6, 697-709.
19. Claiborne, C. F.; McCauley, J. A.; Libby, B. E.; Curtis, N. R.; Diggle, H. J.; Kulagowski, J. J.; Michelson, S. R.; Anderson, K. D.; Claremon, D. A.; Freidinger, R. M.; Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly, T. M.; Condra, C. L.; Bednar, B.; Stump, G. L.; Lynch, J. J.; Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton, N. J. Orally efficacious NR2B-selective NMDA receptor antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 697-700.
20. Naylor-Olsen, A. M.; Ponticello, G. S.; Lewis, S. D.; Mulichak, A. M.; Chen, Z.; Habecker, C. N.; Phillips, B. T.; Sanders, W. M.; Tucker, T. J.; Sharer, J. A.; Vacca, J. P. Identification and SAR for a selective, nonpeptidyl thrombin inhibitor. Bioorg. Med. Chem. Lett. 1998, 8, 1697-1702.
21. Kiss, L.; Cheng, G.; Bednar, B.; Bednar, R. A.; Bennett, P. B.; Kane, S. A.; McIntyre, C. J.; McCauley, J. A.; Koblan, K. S. In vitro characterization of novel NR2B selective NMDA receptor antagonists. Neurochem. Int. 2005, 46, 453-464.
22. Bednar, B.; Cunningham, M. E.; Kiss, L.; Cheng, G.; McCauley, J. A.; Liverton, N. J.; Koblan, K. S. Kinetic characterization of novel NR2B antagonists using fluorescence detection of calcium flux. J. Neurosci. Methods 2004, 137, 247-255.
23. Kr channel. Cell 1995, 81, 299-307.
24. Alanine, A.; Buettelmann, B.; Neidhart, M.-P. H.; Jaeschke, G.; Pinard, E.; Wyler, R. (Hoffmann-La Roche) US 6,432,985, 2002.
25. McCauley, J. A. Amide-containing NR2B/NMDA receptor antagonists Expert Opin. Ther. Pat. 2006, 16, 863-870.
26. De Bruin, M. L.; Pettersson, M.; Meyboom, R. H. B.; Hoes, A. W.; Leufkens, H. G. M. Anti-hERG activity and the risk of drug-induced arrhythmias and sudden death. Eur. Heart J. 2005, 26, 590-597.
27. Raab, C. E.; Butcher, J. W.; Connolly, T. M.; Karczewski, J.; Yu, N. X.; Staskiewicz, S. J.; Liverton, N.; Dean, D. C.; Melillo, D. G. Synthesis of the first sulfur-35-labeled hERG radioligand. Bioorg. Med. Chem. Lett. 2006, 16, 1692-1695.
28. Butcher, J. W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.; Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G. Radioligand and binding assay. PCT Int. Appl. WO 2002005860, 2002.
29. Kimball, S. D.; Das, J.; Lau, W. F.; Hall, S. E.; Han, Wen, C. Preparation of heterocyclic peptide thrombin inhibitors. (Bristol-Myers Squibb), US 5,583,146, 1996.
30. McCauley, J. A.; Theberge, C. R.; Romano, J. J.; Billings, S. B.; Anderson, K. D.; Claremon, D. A.; Freidinger, R. M.; Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly, T. M.; Condra, C. L.; Xia, M.; Cunningham, M. E.; Bednar, B.; Stump, G. L.; Lynch, J. J.; Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton, N. J. NR2B-Selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles. J. Med. Chem. 2004, 47, 2089-2096.
31. Maligres, P. E.; Houpis, I.; Rossen, K.; Molina, A.; Sager, J.; Upadhyay, V.; Wells, K. M.; Reamer, Robert, A.; Lynch, J. E.; Askin, D.; Volante, R. P.; Reider, P. J.; Houghton, P. Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677. Tetrahedron 1997, 53, 10983-10992.
32. Sawayama, T.; Tsukamoto, M.; Sasagawa, T.; Nishimura, K.; Deguchi, T.; Takeyama, K.; Hosoki, K Angiotensin-converting enzyme inhibitors: synthesis and biological activity of N-substituted tripeptide inhibitors. Chem. Pharm. Bull. 1990, 38, 110-115.
33. Mitcheson, J. S.; Chen, J.; Lin, M.; Culberson, C.; Sanguinetti, M. C. A structural basis for drug-induced long QT syndrome. Proc. Natl. Acad. Sci. 2000, 97, 12329-12333.
34. Pearlstein, R. A.; Vaz, R. J.; Kang, J.; Chen, X.-L.; Preobrazhenskaya, M.; Shchekotikhin, A. E.; Korolev, M.; Lysenkova, L. N.; Miroshnikova, O. V.; Hendrix, J.; Rampe, D. Characterization of hERG potassium channel inhibition using CoMSiA QSAR and homology modeling approaches. Bioorg. Med. Chem. Lett. 2003, 13, 1829-1835.
35. Kim, S. H.; Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992, 50, 355-363.
36. LaBuda, C. J.; Little, P. J. Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat. J. Neurosci. Methods 2005, 144, 175-181.
37. Valenti, O.; Marino, M. J.; Wittmann, M.; Lis, E.; DiLella, A. G.; Kinney, G. G.; Conn, P. J. Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J. Neurosci. 2003, 23, 7218-7226.
38. 1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 693-696.
39. Yamazaki, M.; Neway, W. E.; Ohe, T.; Chen, I.-W.; Rowe, J. F.; Hochman, J. H.; Chiba, M.; Lin, J. H. In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predictability of in vivo results. J. Pharm. Exp. Ther. 2001, 296, 723-735.
40. Loftis, J. M., Janowsky, A. The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation and clinical implications. Pharmacol. Ther. 2003, 97, 55-85.
41. Gogas, K. R. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr. Opin. Pharmacol. 2006, 6, 68-74.
42. Wang, H.; Sun, H.; Della Penna, K.; Benz, R. J.; Xu, J.; Gerhold, D. L.; Holder, D. J.; Koblan, K. S. Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience 2002, 114, 529-546.
43. For NR2B binding assay protocol see: Mosser, S. D., Gaul, S. L., Bednar, B., Koblan, K. S. and Bednar, R. A. Automation of in vitro dose-inhibition assays utilizing the tecan genesis and an integrated software package to support the drug discovery process J. Assoc. Laboratory Automation 2003, 8, 54-63.