Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABA(A) ligands of dual functionality

Journal of Medicinal Chemistry

Volumn 42, Issue 7, 1999, Pages 1123-1144

  Jacobsen, E Jon ^a   Stelzer, Lindsay S ^a   TenBrink, Ruth E ^a   Belonga, Kenneth L ^a   Carter, Donald B ^a   Im, Haesook K ^a   Im, Wha Bin ^a   Sethy, Vimala H ^a   Tang, Andy H ^a   VonVoigtlander, Philip F ^a   Petke, James D ^b   Zhong, Wei Zhu ^a   Mickelson, John W ^c  

^a PFIZER INC   (United States)

^b 3M Center Bldg ^*  (United States)

^c 3M COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; 7 CHLORO 5 [(1 (3,5 DIMETHYL)PIPERAZINO)CARBONYL] 4,5 DIHYDROIMIDAZO[1,5 A]QUINOXALINE 3 CARBOXYLIC ACID 1,1 DIMETHYL ETHYL ESTER; BENZODIAZEPINE; ESTER; PENTETRAZOLE; PIPERAZINE IMIDAZO[1,5 A]QUINOXALINE UREA; UNCLASSIFIED DRUG; UREA DERIVATIVE;

AGONIST; ANIMAL EXPERIMENT; ANTICONVULSANT ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; DOSE RESPONSE; DRUG ANTAGONISM; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; LIGAND BINDING; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-ANXIETY AGENTS; ANTICONVULSANTS; ANXIETY; BIOLOGICAL AVAILABILITY; CELL LINE; CEREBELLUM; CONVULSANTS; CYCLIC GMP; DRUG EVALUATION, PRECLINICAL; GABA AGONISTS; IMIDAZOLES; LIGANDS; MALE; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PENTYLENETETRAZOLE; PIPERAZINES; QUINOXALINES; RATS; RATS, INBRED F344; RATS, SPRAGUE-DAWLEY; RECEPTORS, GABA-A; SEIZURES; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 0033535524     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9801307     Document Type: Article

References (78)

1. (a) Squires, R., Ed. GABA and Benzodiazepine Receptors; CRC Press: Boca Raton, FL, 1988; Vol. I, II.
2. (b) Haefely, W. In Benzodiazepines; Beaumont, G., Brandon, S., Leonard, B. E., Eds.; John Wiley and Sons: New York, 1990; pp 1-18.
3. (c) Haefely, W. Partial Agonists of the Benzodiazepine Receptor: From Animal Data to Results in Patients. In Chloride Channels and Their Modulation by Neurotransmitters and Drugs; Biggio, G., Costa, E., Eds.; Raven Press: New York, 1988; pp 275-292.
4. (a) Gardner, C. R. Functional In Vivo Correlates of the Benzodiazepine Agonist-Inverse Agonist Continuum. Prog. Neurobiol. 1988, 31, 425-476.
5. (b) Braeatrup, C.; Nielsen, M. In Receptor Biochemistry and Methodology; Olsen, R. W., Venter, J. C., Eds.; A. R. Liss, Inc.: New York, 1986; Vol. 5, p 167.
6. (c) Bare, T. M.; Resch, J. F.; Patel, J. B. Anxiolytics and Sedative-Hypnotics. In Annual Reports in Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: New York, 1987; Vol. 22, pp 11-20.
7. (d) Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent Advances in the Molecular Pharmacology of Benzodiazepine Receptors and in the Structure-Activity Relationships of Their Agonists and Antagonists. In Advances in Drug Research; Testa, B., Ed.; Academic Press: New York, 1985; Vol. 14, pp 165-322.
8. (e) Braestrup, C.; Honore, T.; Nielsen, M.; Petersen, E. N.; Jensen, L. H. Ligands for Benzodiazepine Receptors With Positive and Negative Efficacy. Biochem. Pharmacol. 1984, 33, 859-862.
9. (a) Petersen, E. N.; Jensen, L. H.; Diejer, J.; Honore, T. New Perspectives in Benzodiazepine Receptor Pharmacology. Pharmacopsychiatry 1986, 19, 4-6.
10. (b) Haefely, W. Psychopharmacology of Anxiety. Eur. Neuropsychopharmacol. 1991, 1, 89-95.
11. For recent reviews, see: (a) Gardner, C. R. A Review of Recently-Developed Ligands for Neuronal Benzodiazepine Receptors and Their Pharmacological Activities. Prog. Neuro-Psychopharmacol, Biol. Psychiatry 1992, 16, 755-781.
12. (b) Gammill, R. B.; Carter, D. B. Neuronal BZD Receptors: New Ligands, Clones and Pharmacology. In Annual Reports Medicinal Chemistry; Bristol, J. A., McCall, J. M., Eds.; Academic Press: New York, 1993; Vol. 28, pp 19-27.
13. (a) Stephens, D. N.; Schneider, H. H.; Kehr, W.; Andrews, J. S.; Rettig, K.-J.; Turski, L.; Schmiechen, R.; Turner, J. D.; Jensen, L. H.; Petersen, E. N.; Honore, T.; Bondo Hansen, J. Abecarnil, a Metabolically Stable, Anxioselective β-Carboline Acting at Benzodiazepine Receptors. J. Pharmacol. Exp. Ther. 1990, 253, 334-343.
14. (b) Turski, L.; Stephens, D. N.; Jensen, L. H.; Petersen, E. N.; Meldrum, B. S.; Patel, S.; Bondo Hansen, J.; Loscher, W.; Schneider, H. H.; Schmiechen, R. Anticonvulsant Action of the β-Carboline Abecarnil: Studies in Rodents and Baboon, Papio papio. J. Pharmacol. Exp. Ther. 1990, 253, 344-352.
15. (c) Ballenger, J. C.; McDonald, S.; Noyes, R.; Rickels, K.; Sussman, N.; Woods, S.; Patin, J.; Singer, J. The First Double-Blind, Placebo-Controlled Trial of a Partial Benzodiazepine Agonist Abecarnil (ZK 112-119) in Generalized Anxiety Disorder. Psychopharmacol. Bull. 1991, 27, 171-179.
16. (a) Pieri, L.; Hunkeler, W.; Jauch, R.; Merz, W. A.; Roncari, G.; Timm, U. Ro 16-6028. Drugs Future 1988, 13, 730-735.
17. (b) Haefely, W.; Martin, J. R.; Schoch, P. Novel Anxiolytics That Act as Partial Agonists at Benzodiazepine Receptors. Trends Pharmacol. Sci. 1990, 11, 452-456.
18. Morimoto, Y.; Fukuda, T.; Yakushiji, T.; Takehara, S.; Anami, K.; Yamamoto, Y.; Yasumatsu, H.; Nakao, T.; Setoguchi, M.; Tahar, T. Anxiolytic Properties of Y-23684, a Benzodiazepine Receptor Partial Agonist in Comparison with Diazepam. Proc. 17th CINP Congr., Kyoto, 1990; Abstr. P-12-2-9, p 169.
19. George, P.; Rossey, G.; Depoortere, H.; Mompon, B.; Allen, J.; Wick, A. Imidazopyridines: Towards Novel Hypnotic and Anxiolytic Drugs. Farmaco 1991, 46 (suppl.), 277-288.
20. (a) Tang, A. H.; Franklin, S. R.; Himes, C. S.; Ho, P. M. Behavioral Effects of U-78875, a Quinoxalinone Anxiolytic with Potent Benzodiazepine Antagonist Activity. J. Pharmacol. Exp. Ther. 1991, 259, 248-254.
21. A Receptors. Mol. Pharmacol. 1992, 42, 294-301.
22. Maryanoff, B. E.; Ho, W.; McComsey, D. F.; Reitz, A. B.; Grous, P. P.; Nortey, S. O.; Shank, R. P.; Dubinsky, B.; Taylor, R. J.; Gardocki, J. F. Potential Anxiolytic Agents. Pyrido[1,2-α]benzimidazoles: A New Structural Class of Ligands for the Benzodiazepine Binding Site on GABA-A Receptors. J. Med. Chem. 1995, 38, 16-20.
23. A Receptor Subunit for Benzodiazepine Pharmacology. Nature 1989, 338, 582-585.
24. (b) Pritchett, D. B.; Seeburg, P. H. γ-Aminobutyric Acid Type A Receptor Point Mutation Increases the Affinity of Compounds for the Benzodiazepine Site. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1421-1425.
25. A Receptor: Is There Hope? J. Neurosci. Res. 1995, 41, 567-571.
26. A Receptor: Is There Hope? J. Neurosci. Res. 1995, 41, 567-571.
27. A/Benzodiazepine Receptor Complex. J. Med. Chem. 1996, 39, 158-175.
28. Ulrich, R. G.; Cramer, C. T.; Bacon, J. A.; Funk, G. M.; Hunt, C. E.; Kholmukhamedov, E.; Petrella, D. K.; Sun, E. L. Interference with Hepatocelluar Metabolism by a Quinoxalinone Anxiolytic and Its Carboxylic Acid Metabolite: What Factors Contribute Towards Cell Death? 1994 Annual Society of Toxicology Meeting, Dallas, TX, Mar. 14-17, 1994.
29. A/Benzodiazepine Receptor Complex. J. Med. Chem. 1996, 39, 3820-3836.
30. A/Benzodiazepine Receptor. J. Med. Chem. 1994, 37, 758-768.
31. Borch, R. F.; Bernstein, M. D.; Durst, H. D. The Cyanoborohydride Anion as a Selective Reducing Agent. J. Am. Chem. Soc. 1971, 93, 2897-2904.
32. (a) Imbach, J. L.; Katritzky, A. R.; Kolinski, R. A. The Conformational Analysis of Heterocyclic Systems. Part VIII. Kinetics of Quaternisation of N-Alkylpiperidines and N-Alkylpiperazines in Acetonitrile. J. Chem. Soc. B 1966, 556-562.
33. (b) Cook, M. J.; Jones, R. A. Y.; Katritzky, A. R.; Moreno Manas, M.; Richards, A. C.; Sparrow, A. J.; Trepanier, D. L. The Conformational Analysis of Saturated Heterocycles. Part XLIX. The Conformation of Ring NH-Groups in Piperazines, Hexahydropyrimidines, Tetrahydro-1,3-oxazines, and Tetrahydro-1,3-thiazines. J. Chem. Soc., Perkin II 1973, 325-331.
34. Braish, T. F.; Fox, D. E. Synthesis of (S,S)-and (R,R)-2-Alkyl-2,5-diazabicyclo[2.2.1]heptanes. J. Org. Chem. 1990, 55, 1684-1687.
35. (a) Cignarella, G.; Nathansohn, G. Bicyclic Homologues of Piperazine. Synthesis of 8-Methyl-3,8-diazabicyclooctanes. I. J. Org. Chem. 1961, 26, 1500-1504.
36. (b) Cignarella, G.; Nathansohn, G.; Occelli, E. Bicyclic Homologues of Piperazine. II. Synthesis of 3,8-Diazabicyclo[3.2.1]octane. New Synthesis of 8-Methyl-3,8-diazabicyclo[3.2.1]octane. J. Org. Chem. 1961, 26, 2747-2751.
37. (c) Blackman, S. W.; Baltzly, R. The Synthesis of 3,8-Diazabicyclo-[3.2.1]octane and Some of Its N-Substituted Derivatives. J. Org. Chem. 1961, 26, 2750-2755.
38. Aspinall, S. R. A Synthesis of Monoketopiperazines. J. Am. Chem. Soc. 1940, 62, 1202-1204.
39. Ishiguro, T.; Matsumura, M. Synthesis of Piperazines. VIII. Synthesis of α(trans)-and β(cis)-2,3-Dimethylpiperazines. Yakugaku Zasshi 1958, 78, 229-231.
40. Yoshioka, T.; Mori, E.; Murayama, K. Studies on Stable Free Radicals. XIII. Synthesis and ESR Spectral Properties of Hindered Piperazine N-Oxyls. Bull. Chem. Soc. Jpn. 1972, 45, 1855-1860.
41. Sudo, R.; Ichihara, S. Reactions of Alicyclic Aminonitrile. Bull. Chem. Soc. Jpn. 1963, 36, 34-37.
42. (a) Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. Asymmetric Synthesis of 2,6-Methylated Piperazines. J. Org. Chem. 1995, 60, 4177-4183.
43. (b) Mickelson, J. W.; Jacobsen, E. J. Asymmetric Synthesis of (2R,6R) and (2S, 6S)-2,6-Dimethylpiperazine. Tetrahedron: Asymmetry 1995, 6, 19-22.
44. Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1-28.
45. 1H NMR analysis of the Mosher amide.
46. Sethy, V. H.; Harris, D. W. Determination of Biological Activity of Alprazolam, Triazolam and Their Metabolites. J. Pharm. Pharmacol. 1982, 34, 115-116.
47. Carter, D. B.; Thomsen, D. R.; Im, W. B.; Lennon, D. J.; Ngo, D. M.; Gale, W.; Im, H. K.; Seeburg, P. H.; Smith, M. W. Functional Expression of GABAA Chloride Channels and Benzodiazepine Binding Sites in Baculovirus Infected Insect Cells. Bio/Technology 1992, 10, 679-681.
48. A Receptor Subunits in a Human Kidney Cell Line. Neurosci. Lett. 1993, 153, 206-209.
49. 5-Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology. J. Neurochem. 1990, 54, 1802-1804.
50. A-Benzodiazepine Receptors Produced in Transfected Cells. Science 1969, 245, 1389-1392.
51. A Receptor Selective for a Behavioral Alcohol Antagonist. Nature 1990, 346, 648-651.
52. - Uptake in Rat Cerebrocortical Membranes. Mol. Pharmacol. 1991, 39, 394-398.
53. - Uptake in Rat Brain Synaptoneurosomes: Evidence for Rapid Desensitization of the GABA Receptor-Coupled Chloride Ion Channel. Mol. Pharmacol. 1986, 30, 419-426.
54. A Receptors. Mol. Pharmacol. 1993, 44, 866-870.
55. - Currents. Mol. Pharmacol. 1991, 39, 691-696.
56. Rudzik, A. D.; Hester, J. B.; Tang, A. H.; Straw, R. N.; Friis, W. Triazolobenzodiazepines, A New Class of Central Nervous System-Depressant Compounds. In The Benzodiazepines; Garatini, S., Mussini, E., Randall, L. O., Eds.; Raven Press: New York, 1973; pp 285-297.
57. Kyburz, E. Serendipity in Drug Discovery. The Case of BzR Ligands. Il Farmaco, 1989, 44, 345-382.
58. A Receptor Subtypes. Brit. J. Pharmacol. 1995, 115, 19-24.
59. 3H)-Flunitrazepam Binding. Drug Dev. Res. 1987, 10, 117-121.
60. (b) Sethy, V. H.; Daenzer, C. L.; Russell, R. R. Interaction of N-Alkylaminobenzophenones with Benzodiazepine Receptors. J. Pharm. Pharmacol. 1983, 35, 194-195.
61. (a) Dinnendahl, V. Effect of Stress on Mouse Brain Cyclic Nucleotide Levels In Vivo. Brain Res. 1976, 100, 716-719.
62. (b) Dinnendahl, V.; Gumulka, S. W. Stress-induced Alterations of Cyclic Nucleotide Levels in Brain: Effect of Centrally Acting Drugs. Psychopharmacology 1977, 52, 243-249.
63. (c) Goldberg N. D.; Haddox, M. K.; Hartle, D. K.; Hadden, J. W. The Biological Role of Cyclic 3′,5′-Guanosine Monophosphate. In Pharmacology and the Future of Man; Maxwell, R. A., Acheson, G. H., Eds.; Karger: Basel, 1972; pp 146-169.
64. Sethy, V. H.; Oien, T. T. Role of cGMP in the Mechanism of Anxiolytic Activity of U-78875. Pharmacol. Biochem. Behavior. 1991, 39, 379-382.
65. (a) VonVoigtlander, P. F.; Lewis, R. A. A Rapid Screening Method for the Assessment of Benzodiazepine Receptor-Related Physical Dependence in Mice. J. Pharmacol. Methods 1991, 26, 1-5.
66. (b) Fialip, J.; Aumaitre, O.; Eschalier, A.; Maradeix, B.; Dordain, G.; Lavarenne, J. Benzodiazepine Withdrawal Seizures: Analysis of 48 Case Reports. Clin. Neuropharmacol. 1987, 10, 538-544.
67. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. MacroModel-An Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
68. Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. An All Atom Force Field for Simulations of Proteins and Nucleic Acids. J. Comput. Chem. 1986, 7, 230-252.
69. 2 Torsional Terms. J. Am. Chem. Soc. 1977, 99, 8127-8134.
70. Chang, G.; Guida, W. C.; Still, W. C. An Internal Coordinate Monte Carlo Method for Searching Conformational Space. J. Am. Chem. Soc. 1989, 111, 4379-4386.
71. Stewart, J. J. P. MOPAC, A Semiempirical Molecular Orbital Program. J. Comput.-Aided Mol. Des. 1990, 4, 1-105.
72. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. AM1: A New General Purpose Quantum Mechanical Molecular Model. J. Am. Chem. Soc. 1986, 107, 3902-3909.
73. Tebib, S.; Bourguignon, J.-J.; Wermuth, C.-G.; The Active Analogue Approach Applied to the Pharmacophore Identification of Benzodiazepine Receptor Ligands. J. Comput.-Aided Mol. Des. 1987, 1, 153-170.
74. Zhang, W.; Koehler, K. F.; Zhang, P.; Cook, J. M. Development of a Comprehensive Pharmacophore Model for the Benzodiazepine Receptor. Drug Des. Discovery 1995, 12, 193-248.
75. Dale, J. A.; Mosher, H. S. Nuclear Magnetic Resonance Enantiomer Reagents. Configurational Correlations via Nuclear Magnetic Resonance Chemical Shifts of Diastereomeric Mandelate, O-Methylmandelate, and α-Methoxy-α-trifluoromethylphenylacetate (MTPA) Esters. J. Am. Chem. Soc. 1973, 95, 512-519.
76. Burkard, W. P.; Bonetti, E. P.; Haefely, W. The Benzodiazepine Antagonist Ro 15-1788 Reverses the Effect of Methyl-β-carboline-3-carboxylate but not of Harmaline on Cerebellar cGMP and Motor Performance in Mice. Eur. J. Pharmacol. 1986, 109, 241-247.
77. Waynforth, H. B. In Experimental and Surgical Technique in the Rat; Academic Press: London, 1980; pp 50-57, 72-74.
78. Gibaldi, M.; Perrier, D. In Pharmacokinetics, 2nd ed.; Swarbrick, J., Ed.; Marcel Dekker: New York, 1982; pp 5, 411.