Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2

Journal of Medicinal Chemistry

Volumn 58, Issue 22, 2015, Pages 9027-9040

  Felts, Andrew S ^a   Rodriguez, Alice L ^a   Smith, Katrina A ^a   Engers, Julie L ^a   Morrison, Ryan D ^a,c   Byers, Frank W ^a   Blobaum, Anna L ^a   Locuson, Charles W ^a,d   Chang, Sichen ^a   Venable, Daryl F ^a   Niswender, Colleen M ^a   Daniels, J Scott ^a,c   Conn, P Jeffrey ^a   Lindsley, Craig W ^a,b   Emmitte, Kyle A ^a,b,e  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY   (United States)

^c Sano Informed Prescribing   (United States)

^d Takeda Pharmaceuticals   (United Kingdom)

^e UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 FLUOROPHENYL) 4 OXO 6 VINYL 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; 1 (4 FLUOROPHENYL) 6 FORMYL 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; 6 BROMO 1 (4 FLUOROPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; 6 [(CIS 2,6 DIMETHYLMORPHOLINO)METHYL] 1 (4 FLUOROPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; AMIDE; CARBENE; ETHYL 3 (5 BROMO 2 FLUOROPHENYL) 3 OXOPROPANOATE; ETHYL 6 BROMO 1 (4 FLUOROPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLATE; HETEROCYCLIC AMINE; METABOTROPIC RECEPTOR 2; PALLADIUM; QUINOLINE DERIVATIVE; TERTIARY AMINE; UNCLASSIFIED DRUG; METABOTROPIC RECEPTOR; METABOTROPIC RECEPTOR 3; MUSCARINIC M1 RECEPTOR; PROTEIN BINDING; QUINOLONE DERIVATIVE; VU6001192;

ALLOSTERISM; AMINATION; ARTICLE; BRAIN-TO-PLASMA RATIO; BUCHWALD HARTWIG AMINATION; CALCIUM MOBILIZATION; DIHYDROXYLATION; DRUG DESIGN; DRUG HALF LIFE; DRUG METABOLISM ASSAY; DRUG PENETRATION; DRUG SYNTHESIS; HEPATIC CLEARANCE; HYDROGENATION; INTRINSIC CLEARANCE; LIPOPHILICITY; LITHIATION; LIVER MICROSOME; METABOLIC STABILITY; MICROWAVE IRRADIATION; MITSUNOBU REACTION; MOUSE; NONHUMAN; PROTEIN BINDING; RAT; SONOGASHIRA REACTION; SUZUKI REACTION; TISSUE DISTRIBUTION; VOLUME OF DISTRIBUTION AT STEADY-STATE; ANIMAL; ANTAGONISTS AND INHIBITORS; CENTRAL NERVOUS SYSTEM; DRUG DEVELOPMENT; DRUG EFFECTS; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANIMALS; CENTRAL NERVOUS SYSTEM; DRUG DISCOVERY; MICE; PROTEIN BINDING; QUINOLINES; QUINOLONES; RATS; RECEPTOR, MUSCARINIC M1; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84948807651     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01371     Document Type: Article

References (63)

1. Niswender, C. M.; Conn, P. J. Metabotropic glutamate receptors: Physiology, pharmacology, and disease Annu. Rev. Pharmacol. Toxicol. 2010, 50, 295-322 10.1146/annurev.pharmtox.011008.145533
2. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Pharmacological agents acting at subtypes of metabotropic glutamate receptors Neuropharmacology 1999, 38, 1431-1476 10.1016/S0028-3908(99)00092-1
3. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237 10.1146/annurev.pharmtox.37.1.205
4. Chaki, S.; Ago, Y.; Palucha-Paniewiera, A.; Matrisciano, F.; Pilc, A. mGlu2/3 and mGlu5 receptors: Potential targets for novel antidepressants Neuropharmacology 2013, 66, 40-52 10.1016/j.neuropharm.2012.05.022
5. Palucha, A.; Pilc, A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs Pharmacol. Ther. 2007, 115, 116-147 10.1016/j.pharmthera.2007.04.007
6. Ellaithy, A.; Younkin, J.; Gónzalez-Maeso, J.; Logothetis, D. E. Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment Trends Neurosci. 2015, 38, 506-516 10.1016/j.tins.2015.06.002
7. Célanire, S.; Sebhat, I.; Wichmann, J.; Mayer, S.; Schann, S.; Gatti, S. Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005-present) Expert Opin. Ther. Pat. 2015, 25, 69-90 10.1517/13543776.2014.983899
8. Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Kennedy, J. H.; Wright, R. A.; Johnson, B. G.; Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp, D. D. 2-Substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability J. Med. Chem. 1998, 41, 358-378 10.1021/jm970498o
9. Chaki, S.; Yoshikawa, R.; Hirota, S.; Shimazaki, T.; Maeda, M.; Kawashima, N.; Yoshimizu, T.; Yasuhara, A.; Sakagami, K.; Okuyama, S.; Nakanishi, S.; Nakazato, A. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity Neuropharmacology 2004, 46, 457-467 10.1016/j.neuropharm.2003.10.009
10. Bespalov, A. Y.; van Gaalen, M. M.; Sukhotina, I. A.; Wicke, K.; Mezler, M.; Schoemaker, H.; Gross, G. Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression Eur. J. Pharmacol. 2008, 592, 96-102 10.1016/j.ejphar.2008.06.089
11. Shimazaki, T.; Iijima, M.; Chaki, S. Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test Eur. J. Pharmacol. 2004, 501, 121-125 10.1016/j.ejphar.2004.08.016
12. Yoshimizu, T.; Shimazaki, T.; Ito, A.; Chaki, S. An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Psychopharmacology 2006, 186, 587?593.
13. Higgins, G. A.; Ballard, T. M.; Kew, J. N.; Richards, J. G.; Kemp, J. A.; Adam, G.; Woltering, T.; Nakanishi, S.; Mutel, V. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent Neuropharmacology 2004, 46, 907-917 10.1016/j.neuropharm.2004.01.018
14. Kim, S. H.; Steele, J. W.; Lee, S. W.; Clemenson, G. D.; Carter, T. A.; Treuner, K.; Gadient, R.; Wedel, P.; Glabe, C.; Barlow, C.; Ehrlich, M. E.; Gage, F. H.; Gandy, S. Proneurogenic group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse Mol. Psychiatry 2014, 19, 1235-1242 10.1038/mp.2014.87
15. 42 from isolated intact nerve terminals J. Neurosci. 2010, 30, 3870-3875 10.1523/JNEUROSCI.4717-09.2010
16. Yoshimizu, T.; Chaki, S. Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039 Biochem. Biophys. Res. Commun. 2004, 315, 493-496 10.1016/j.bbrc.2004.01.073
17. Gleason, S. D.; Li, X.; Smith, I. A.; Ephlin, J. D.; Wang, X. S.; Heinz, B. A.; Carter, J. H.; Baez, M.; Yu, J.; Bender, D. M.; Witkin, J. M. mGlu2/3 agonist-induced hyperthermia: An in vivo assay for detection of mGlu2/3 receptor antagonism and its relation to antidepressant-like efficacy in mice CNS Neurol. Disord.: Drug Targets 2013, 12, 554-566 10.2174/18715273113129990079
18. Koike, H.; Fukumoto, K.; Iijima, M.; Chaki, S. Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression Behav. Brain Res. 2013, 238, 48-52 10.1016/j.bbr.2012.10.023
19. Koike, H.; Iijima, M.; Chaki, S. Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists Neuropharmacology 2011, 61, 1419-1423 10.1016/j.neuropharm.2011.08.034
20. Karasawa, J.; Shimazaki, T.; Kawashima, N.; Chaki, S. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist Brain Res. 2005, 1042, 92-98 10.1016/j.brainres.2005.02.032
21. Iijima, M.; Koike, H.; Chaki, S. Effect of an mGlu2/3 receptor antagonist on depressive behavior induced by withdrawal from chronic treatment with methamphetamine Behav. Brain Res. 2013, 246, 24-28 10.1016/j.bbr.2013.02.039
22. Markou, A. Metabotropic glutamate receptor antagonists: Novel therapeutics for nicotine dependence and depression? Biol. Psychiatry 2007, 61, 17-22 10.1016/j.biopsych.2006.03.053
23. Ago, Y.; Yano, K.; Araki, R.; Hiramatsu, N.; Kita, Y.; Kawasaki, T.; Onoe, H.; Chaki, S.; Nakazato, A.; Hashimoto, H.; Baba, A.; Takuma, K.; Matsuda, T. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice Neuropharmacology 2013, 65, 29-38 10.1016/j.neuropharm.2012.09.008
24. Dwyer, J. M.; Lepack, A. E.; Duman, R. S. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure J. Mol. Psychiatry 2013, 1, 15 10.1186/2049-9256-1-15
25. Campo, B.; Kalinichev, M.; Lambeng, N.; Yacoubi, M. E.; Royer-Urios, I.; Schneider, M.; Legrand, C.; Parron, D.; Girard, F.; Bessif, A.; Poli, S.; Vaugeois, J.-M.; Le Poul, E.; Célanire, S. Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression J. Neurogenet. 2011, 25, 152-166 10.3109/01677063.2011.627485
26. Pritchett, D.; Jagannath, A.; Brown, L. A.; Tam, S. K. E.; Hasan, S.; Gatti, S.; Harrison, P. J.; Bannerman, D. M.; Foster, R. G.; Peirson, S. N. Deletion of metabotropic glutamate receptors 2 and 3 (mGlu2 & mGlu3) in mice disrupts sleep and wheel-running activity, and increases the sensitivity of the circadian system to light PLoS One 2015, 10, e0125523 10.1371/journal.pone.0125523
27. Woltering, T. J.; Wichmann, J.; Goetschi, E.; Knoflach, F.; Ballard, T. M.; Huwyler, J.; Gatti, S. Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists Bioorg. Med. Chem. Lett. 2010, 20, 6969-6974 10.1016/j.bmcl.2010.09.125
28. Yacoubi, M. E.; Vaugeois, J.-M.; Kalinichev, M.; Célanire, S.; Parron, D.; Le Poul, E.; Campo, B. Effects of a mGluR2/3 negative allosteric modulator and a reference mGluR2/3 orthosteric antagonist in a genetic mouse model of depression. In Behavioral Studies of Mood Disorders, Proceedings of the 40th Annual Meeting of the Society for Neuroscience, San Diego, CA, Nov 13-17, 2010; Society for Neuroscience: Washington, DC, 2010; 886.14/VV7.
29. Goeldner, C.; Ballard, T. M.; Knoflach, F.; Wichmann, J.; Gatti, S.; Umbricht, D. Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target Neuropharmacology 2013, 64, 337-346 10.1016/j.neuropharm.2012.08.001
30. Kalinichev, M.; Campo, B.; Lambeng, N.; Célanire, S.; Schneider, M.; Bessif, A.; Royer-Urios, I.; Parron, D.; Legrand, C.; Mahious, N.; Girard, F.; Le Poul, E. An mGluR2/3 negative allosteric modulator improves recognition memory assessed by natural forgetting in the novel object recognition test in rats. In Memory Consolidation and Reconsolidation: Molecular Mechanisms II, Proceedings of the 40th Annual Meeting of the Society for Neuroscience, San Diego, CA, Nov 13-17, 2010; Society for Neuroscience: Washington, DC, 2010; 406.9/MMM57.
31. Structure of decoglurantis disclosed in Recommended International Nonproprietary Names (INN). WHO Drug Information; World Health Organization: Geneva, Switzerland, 2013; Vol. 27, No. 3, p 150.
32. ClinicalTrials.gov. ARTDeCo study: A study of RO4995819 in patients with major depressive disorder and inadequate response to ongoing antidepressant treatment. https://www.clinicaltrials.gov/ct2/show/NCT01457677 (accessed August 12, 2015).
33. 5 PAM Bioorg. Med. Chem. Lett. 2012, 22, 3921-3925 10.1016/j.bmcl.2012.04.112
34. 3 selective and CNS penetrant negative allosteric modulator (NAM) J. Med. Chem. 2013, 56, 5208-5212 10.1021/jm400439t
35. Walker, A. G.; Wenthur, C. J.; Xiang, Z.; Rook, J. M.; Emmitte, K. A.; Niswender, C. M.; Lindsley, C. W.; Conn, P. J. Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 1196-1201 10.1073/pnas.1416196112
36. Engers, J. L.; Rodriguez, A. L.; Konkol, L. C.; Morrison, R. D.; Thompson, A. D.; Byers, F. W.; Blobaum, A. L.; Chang, S.; Venable, D. F.; Loch, M. T.; Niswender, C. M.; Daniels, J. S.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A. Discovery of a selective and CNS penetrant negative allosteric modulator of metabotropic glutamate receptor subtype 3 with antidepressant and anxiolytic activity in rodents J. Med. Chem. 2015, 58, 7485-7500 10.1021/acs.jmedchem.5b01005
37. Bungard, C. J.; Converso, A.; De Leon, P.; Hanney, B.; Hartingh, T. J.; Manikowski, J. J.; Manley, P. J.; Meissner, R.; Meng, Z.; Perkins, J. J.; Rudd, M. T.; Shu, Y. Quinoline carboxamide and quinoline carbonitrile derivatives as mGluR2-negative allosteric modulators, compositions, and their use. PCT Int. Pat. Appl. WO 2013/066736 A1, May 10, 2013.
38. 1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2011, 21, 2769-2772 10.1016/j.bmcl.2010.10.028
39. 1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2010, 20, 2533-2537 10.1016/j.bmcl.2010.02.096
40. 1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2010, 20, 531-536 10.1016/j.bmcl.2009.11.100
41. Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. The selective reaction of aryl halides with KOH: Synthesis of phenols, aromatic ethers, and benzofurans J. Am. Chem. Soc. 2006, 128, 10694-10695 10.1021/ja0639719
42. But, T. Y. S.; Toy, P. H. The Mitsunobu reaction: Origin, mechanism, improvements, and applications Chem.-Asian J. 2007, 2, 1340-1355 10.1002/asia.200700182
43. Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination Angew. Chem., Int. Ed. 2008, 47, 6338-6361 10.1002/anie.200800497
44. Molander, G. A.; Rodríguez Rivero, M. Suzuki cross-coupling reactions of potassium alkenyltrifluoroborates Org. Lett. 2002, 4, 107-109 10.1021/ol0169729
45. Thorand, S.; Krause, N. Improved procedures for the palladium-catalyzed coupling of terminal alkynes with aryl bromides (Sonogashira coupling) J. Org. Chem. 1998, 63, 8551-8553 10.1021/jo9808021
46. 1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold J. Med. Chem. 2011, 54, 4773-4780 10.1021/jm200400m
47. 1 allosteric modulators: SAR in the piperidine series Bioorg. Med. Chem. Lett. 2011, 21, 1710-1715 10.1016/j.bmcl.2011.01.094
48. 1 allosteric muscarinic receptor modulators ACS Med. Chem. Lett. 2010, 1, 263-267 10.1021/ml100095k
49. Obach, R. S. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes Drug Metab. Dispos. 1999, 27, 1350-1359
50. Kalvass, J. C.; Maurer, T. S. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery Biopharm. Drug Dispos. 2002, 23, 327-338 10.1002/bdd.325
51. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 10.1038/nrd2445
52. 5) ACS Chem. Neurosci. 2011, 2, 450-470 10.1021/cn2000519
53. Robichaud, A. J.; Engers, D. W.; Lindsley, C. W.; Hopkins, C. R. Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics ACS Chem. Neurosci. 2011, 2, 433-449 10.1021/cn200043e
54. 5 ACS Chem. Neurosci. 2011, 2, 411-432 10.1021/cn2000266
55. Bridges, T. M.; Morrison, R. D.; Byers, F. W.; Luo, S.; Daniels, J. S. Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat Pharmacol. Res. Perspect. 2014, 2, e00077 10.1002/prp2.77
56. Di, L.; Rong, H.; Feng, B. Demystifying brain penetration in central nervous system drug discovery J. Med. Chem. 2013, 56, 2-12 10.1021/jm301297f
57. Wang, Q.; Rager, J. D.; Weinstein, K.; Kardos, P. S.; Dobson, G. L.; Li, J.; Hidalgo, I. J. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier Int. J. Pharm. 2005, 288, 349-359 10.1016/j.ijpharm.2004.10.007
58. Noetzel, M. J.; Rook, J. M.; Vinson, P. N.; Cho, H.; Days, E.; Zhou, Y.; Rodriguez, A. L.; Lavreysen, H.; Stauffer, S. R.; Niswender, C. M.; Xiang, Z.; Daniels, J. S.; Lindsley, C. W.; Weaver, C. D.; Conn, P. J. Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function Mol. Pharmacol. 2012, 81, 120-133 10.1124/mol.111.075184
59. Niswender, C. M.; Johnson, K. A.; Luo, Q.; Ayala, J. E.; Kim, C.; Conn, P. J.; Weaver, C. D. A novel assay of Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors Mol. Pharmacol. 2008, 73, 1213-1224 10.1124/mol.107.041053
60. 1 positive allosteric modulator ML169 ACS Chem. Neurosci. 2012, 3, 884-895 10.1021/cn300068s
61. LeadProfilingScreen (catalog no. 68), Eurofins Panlabs, Inc. (www.eurofinspanlabs.com).
62. Bridges, T. M.; Rook, J. M.; Noetzel, M. J.; Morrison, R. D.; Zhou, Y.; Gogliotti, R. D.; Vinson, P. N.; Xiang, Z.; Jones, C. K.; Niswender, C. M.; Lindsley, C. W.; Stauffer, S. L.; Conn, P. J.; Daniels, J. S. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism Drug Metab. Dispos. 2013, 41, 1703-1714 10.1124/dmd.113.052084
63. Kallem, R.; Kulkarni, C. P.; Patel, D.; Thakur, M.; Sinz, M.; Singh, S. P.; Mahammad, S. S.; Mandlekar, S. A simplified protocol employing elacridar in rodents: A screening model in drug discovery to assess P-gp mediated efflux at the blood brain barrier Drug Metab. Lett. 2012, 6, 134-144 10.2174/187231212804096682