5-(Piperidin-2-yl)- and 5-(homopiperidin-2-yl)-1,4-benzodiazepines: High-affinity, basic ligands for the cholecystokinin-B receptor

Journal of Medicinal Chemistry

Volumn 40, Issue 16, 1997, Pages 2491-2501

  Castro, José L ^a   Broughton, Howard B ^a   Russell, Michael G N ^a   Rathbone, Denise ^a   Watt, Alan P ^a   Ball, Richard G ^b   Chapman, Kerry L ^a   Patel, Smita ^a   Smith, Alison J ^a   Marshall, George R ^a   Matassa, Victor G ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZODIAZEPINE DERIVATIVE; CHOLECYSTOKININ B RECEPTOR;

ANXIETY NEUROSIS; ARTICLE; BINDING AFFINITY; CRYSTALLOGRAPHY; DEPRESSION; LIGAND BINDING; LIPOPHILICITY; PROTEIN ANALYSIS; RACEMIC MIXTURE; RECEPTOR BINDING; SITE DIRECTED MUTAGENESIS;

ANIMALS; BENZODIAZEPINES; BENZODIAZEPINONES; DRUG DESIGN; GUINEA PIGS; LIGANDS; MODELS, MOLECULAR; PHENYLUREA COMPOUNDS; PIPERIDINES; RATS; RECEPTOR, CHOLECYSTOKININ A; RECEPTOR, CHOLECYSTOKININ B; RECEPTORS, CHOLECYSTOKININ; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 15444358348     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9608523     Document Type: Article

References (55)

1. Castro, J. L.; Ball, R. G.; Broughton, H. B.; Russell, M. G. N.; Rathbone, D.; Watt, A. P.; Baker, R.; Chapman, K. L.; Fletcher, A. E.; Patel, S.; Smith, A. J.; Marshall, G. R.; Ryecroft, W.; Matassa, V. G. Controlled Modification of Acidity in CCK-B Receptor Antagonists: N-[1,4-Benzodiazepin-3-yl]-N'-[3-{(tetrazol-5-yl)amino}phenyl] Ureas. J. Med. Chem. 1996, 37, 842-849 and references therein.
2. 1A Receptor Antagonists (+)-WAY100135 and WAY100635. Neuropharmacology 1995, 34, 805-811.
3. A/B Receptor Antagonists. Eur. J. Pharmacol. 1995, 286, 185-191.
4. A and CCKB Receptors in the Modulation of Endogenous Enkephalin Antidepressant-like Effects. Psychopharmacology 1995, 120, 400-408.
5. B Receptor Antagonist LY288513 on Conditioned Fear Stress in Rats. Eur. J. Pharmacol. 1996, 300, 25-31.
6. 1 Receptor Interactions in the Rat. Eur. J. Pharmacol. 1996, 298, 7-15.
7. 3 Dorsal Hyppocampus. Naunyn Schmiedeberg's Arch. Pharmacol. 1996, 353, 382-390.
8. Deweerth, A.; Pisegna, J. R.; Huppi, K.; Wank, S. A. Molecular Cloning, Functional Expression and Chromosomal Localization of the Human Cholecystokinin Type-A Receptor. Biochem. Biophys. Res. Commun. 1993, 194, 811-818.
9. (a) Song, I.; Brown, D. R.; Wiltshire, R. N.; Gantz, L; Trent, J. M.; Yamada, T. The Human Gastrin/Cholecystokinin Type B Receptor Gene; Alternative Splice Donor Site in Exon 4 Generates two Variant mRNAs. Prof. Natl. Acad. Sci. U.S.A. 1993, 90, 9085-9089.
10. (b) Ito, M.; Matsui, T.; Taniguchi, T.; Tsukamoto, T.; Murayama, T.; Arima, N.; Nakata, H.; Chiba, T. Chihara, K. Functional Characterization of a Human Brain Cholecystokinin-B Receptor: A Trophic Effect of Choleeystokinin and Gastrin. J. Biol. Chem. 1993, 268, 18300-18305.
11. (c) Lee, Y. M.; Beinborn, M.; McBride, E. W.; Lu, M.; Kolakowski, L. F. J.; Kopin, A. S. The Human Brain Cholecystokinin-B/Gastrin Receptor: Cloning and Characterization. J. Biol. Chem. 1993, 268, 8164-8169.
12. (a) Kopin, A. S.; McBride. E. W.; Quinn, S. M.; Kolakowski, L. F.; Beinborn, M. The Role of the Cholecystokinin-B/Gastrin Receptor Transmenbrane Domains in Determining Affinity for Subtype-Selective Ligands. J. Biol. Chem. 1995, 270, 5019-5023.
13. 100 in the Second Transmembrane Domain of the Cholecystokinin B Receptor Increases Antagonist Binding and Reduces Signal Transduction. Mol. Pharmacol. 1995, 48, 783-789.
14. B versus CCKA Receptor Antagonist Selectivity. Eur. J. Pharmacol. 1996, 296, 97-106.
15. (a) Rault, S.; Bureau, R.; Pilo, J. C.; Robba, M. Comparative Molecular Field Analysis of CCK-A Antagonists Using Field-Fit as an Alignment Technique. A Convenient Guide to Design New CCK-A Ligands. J. Comput.-Aided Mol. Des. 1992, 6, 553-568.
16. (b) Tokarski, J. S.; Hopfinger, A. J. Three-Dimensional Molecular Shape Analysis-Quantitative Structure-Activity Relationship of a Series of Cholecystokinin-A Receptor Antagonists. J. Med. Chem. 1994, 37, 3639-3654.
17. (c) Van der Bent, A.; IJzerman, A. P.; Soudijn, W. Molecular Modelling of CCK-A Receptors. Drug Des. Discovery 1994, 12, 129-148.
18. (a) Nikiforovich, G. V.; Hruby, V. J. Models for the A-Receptor-Bound and B-Receptor-Bound Conformations of CCK-8. Biochem. Biophys. Res. Commun. 1993, 194, 9-16.
19. (b) Greco, G.; Novellino, E.; Silipo, C.; Vittoria, A. Molecular Modelling Studies with CCK-B Receptor Antagonists. In Trends in QSAR Molecular Modelling, 92; Wermuth, C. G., Ed.; ESCOM Science Publishers: BV, Amsterdam, 1992; pp 466-470.
20. (c) Bureau, R.; Robba, M. Comparative Molecular Field Analysis of CCK-B Antagonists. Eur. J. Med. Chem. 1994, 29, 487-494.
21. (d) Gupta, S. P.; Mulchandani, V.; Das, S.; Subbiah, A.; Reddy, D. N.; Sinha, J. A. Quantitative Structure-Activity Relationship Study on Some Cholecystokinin Antagonists. Quant. Struct.-Act. Relat. 1995, 14, 437-443.
22. B Selective Receptor Ligands: Novel 1,3,5-Trisubstituted Benzazepin-2-ones. Bioorg. Med. Chem. Lett. 1995, 5, 1421-1426.
23. B Receptor Antagonists that Contain Lipophilic Carboxylate Surrogates. Bioorg. Med. Chem. Lett. 1995, 5, 2303-2308.
24. B/ Gastrin Receptor Antagonists. Bioorg. Med. Chem. Lett. 1995, 5, 3023-3026.
25. 5-(3-Azabicyclo[3.2.2]nonan-3-yl) Analogue of Devazepide, a Selective, High Affinity Antagonist for the Cholecyctokinin-A Receptor. Med. Chem. Res. 1996, 312-317.
26. (a) Lowe, J. A., III; Drozda, S. E.; McLean, S.; Bryce, D. K.; Crawford, R. T.; Zorn, S.; Morrone, J.; Appeton, T. A.; Lombardo, F. A Water Soluble Benzodiazepine Cholecystokinin-B Receptor Antagonist. Bioorg. Med. Chem. Lett. 1995, 5, 1933-1936.
27. B Ligands with Anxiolytic-Like Properties. Bioorg. Med. Chem. Lett. 1995, 5, 3057-3062.
28. (c) Kalindjian, S. B.; Buck, I. M.; Cushnir, J. R.; Dunstone, D. J.; Hudson, M. L.; Low, C. M. R.; McDonald, I. M.; Pether, M. J.; Steel, K. I. M.; Tozer, M. J. Improving the Affinity and Selectivity of a Nonpeptide Series of Cholecystokinin-B/Gastrin Receptor Antagonists Based on the Dibenzobicyclo[2.2.2]octane Skeleton. J. Med. Chem. 1995, 38, 4294-4302.
29. (d) Curotto, G.; Donati, D.; Pentassuglia, G.; Ursini, A. 1,5-Benzodiazepines as CCK-B Antagonists. Effect of Halogen Substitution at the Benzo-fused Ring on Potency and Selectivity. Bioorg. Med. Chem. Lett. 1995, 5, 3011-3016.
30. (e) Aquino, C. J.; Armour, D. R.; Berman, J. M.; Birkemo, L. S.; Carr, R. A. E.; Croom, D. K.; Dezube, M.; Dougherty, R. W., Jr.; Ervin, G. N.; et al. Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity.1. Optimization of the Agonist "trigger". J. Med. Chem. 1996, 39, 562-569.
31. (f) Semple, G.; Ryder, H.; Kendrick, D. A.; Szelke, M.; Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. Synthesis and Biological Activities of 1-Alkylcarbonylmethyl Analogues of YM022. Bioorg. Med. Chem. Lett. 1996, 6, 51-54.
32. (g) Semple, G.; Ryder, H.; Kendrick, D. A.; Szelke, M.; Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. Synthesis and Biological Activity of 5-Heteroaryl Benzodiazepines: Analogues of YM022. Bioorg. Med. Chem. Lett. 1996, 6, 55-58.
33. (h) Kalindjian. S. B.; Buck, I. M.; Davis, M. R.; Dunstone, D. J.; Hudson, M. L.; Low, C. M. R.; McDonald, I. M.; Pether, M. J.; Steel, K. I. M.; Tzer, M. J.; Vinter, J. G. Non-Peptide Cholecystokinin-B/Gastrin Receptor Antagonists Based on Bicyclic, Heteroaromatic Skeletons. J. Med. Chem. 1996, 39, 1806-1815.
34. (i) Henke, B. R.; Wilson, T. M.; Sugg, E. E.; Croom, D. K.; Dougherty, R. W., Jr.; Queen, K. L.; Birkemo, L. S.; Ervin, G. N.; Grizzle, M. K.; Johnson, M. F.; James, M. K. 3-(1H-Indazol-3-ylmethyl)-1,5-benzodiazepines: CCK-A Agonists that Demonstrate Oral Activity as Satiety Agents. J. Med. Chem. 1996, 39, 2655-2658.
35. (j)-Wilson, T. M.; Henke, B. R.; Momtahen, T. M.; Myers, P. L.; Sugg, E. E.; Unwalla, R. J.; Croom, D. K.; Dougherty, R. W.; Grizzle, M. K.; Johnson, M. F.; Queen, K. L.; Rimele, T. J.; Yingling, J. D.; James, M. K. 3-[2-(N-Phenylacetamide)]-1,5- benzodiazepines: Orally Active, Binding Selective CCK-A Agonists. J. Med. Chem. 1996, 39, 3030-3034.
36. (k) Satoh, M.; Okamato, Y.; Koshio, H.; Semple, G.; Mase, T.; Miyata, K.; Akuzawa, S.; Nishida, A.; Ohta, M. Biological Activity of Analogues of YM022. Novel (3-Amino Substituted Phenyl)urea Derivatives of 1,4-benzodiazepin-2-one as Gastrin/Cholecystokinin Receptor Antagonists. Chem. Pharm. Bull. 1996, 44, 1412-1414.
37. B/Gastrin Receptor. Bioorg. Med. Chem. Lett. 1993, 3, 1919-1993.
38. B/Gastrin Receptor Antagonists Containing a Cationic Solubilising Group. J. Med. Chem. 1994, 37, 719-721.
39. Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Whitter, W. L.; Garsky, V. M.; Gilbert, K. F.; Leighton, J. L.; Carson, K. L.; Mellin, E. C.; Veber, D. F.; Chang, R. S. L.; Lotti, V. J.; Freedman, S. B.; Smith, A. J.; Patel, S.; Anderson, P. S.; Freidinger, R. M. Development of 1,4-Benzodiazepine Cholecystokinin Type B Antagonists. J. Med. Chem. 1993, 36, 4276-4292.
40. Guzman, A.; Quintero, C.; Muchowski, J. M. Alkylation of α-tert-Butoxycarbonylamino Ketone Enolate Anions. A Useful Synthesis of α-Alkyl-α-amino Ketones, 2-Acylpyrrolidines, and 2-Acylpiperidines. Can. J. Chem. 1991, 69, 2059-2063.
41. (a) Jung, M. E.; Gervay, J. gem-Dialkyl Effect in the Intramolecular Diels-Alder Reaction of 2-Furfuryl Methyl Fumarates. The Reactive Rotamer Effect, Enthalpic Basis for Acceleration, and Evidence for a Polar transition State. J. Am. Chem. Soc. 1991, 113, 224-232.
42. (b) Kirby, A. J. Effective Molarities for Intramolecular Reactions. Adv. Phys. Org. Chem. 1980, 17, 183-278.
43. Vecchietti, V.; Colle, R.; Dondio, G.; Giordani, A. Preparation of 1-Acyl-2-(pyrrolidinomethyl)piperidines and analogues as analgesics and diuretics. Eur. Pat. Appl. EP 447704 A1, 1991.
44. -, TPAP: A Catalytic Oxidant for Organic Synthesis. Synthesis 1994, 639-666.
45. It has been established that the CCK-A/CCK-B selectivity for benzodiazepine-based compounds such as L-365,260 is not a species effect. For example this compound discriminates between CCK-A and CCK-B receptors within the same species, and the affinities for these receptors are very similar across species (e.g., mouse, rat, guinea pig, human: Lotthi, V. J.; Chang, S. L. Eur. J. Pharmacol. 1989, 162, 273-280). This has also been demonstrated for the CCK-A selective compound Devazepide (MK-329): Freidinger, R. M.; Berlin, R. G. Drugs Future 1989, 14, 862-866.
46. It has been established that the CCK-A/CCK-B selectivity for benzodiazepine-based compounds such as L-365,260 is not a species effect. For example this compound discriminates between CCK-A and CCK-B receptors within the same species, and the affinities for these receptors are very similar across species (e.g., mouse, rat, guinea pig, human: Lotthi, V. J.; Chang, S. L. Eur. J. Pharmacol. 1989, 162, 273-280). This has also been demonstrated for the CCK-A selective compound Devazepide (MK-329): Freidinger, R. M.; Berlin, R. G. Drugs Future 1989, 14, 862-866.
47. 50s: 2300, 290, and 240 nM, respectively): Chambers, M. S., unpublished results. (Graph Presented)
48. (a) Yasuda, M. Dissociation Constants of Some Carboxylic Acids in Mixed Aqueous Solvents. Bull. Chem. Soc. Jpn. 1959, 32, 429-432.
49. (b) Shedlovsky, T.; Kay, R. L. The Ionisation Constant of Acetic Acid in Water-Methanol Mixtures at 25 °C from Conductance Measurements. J. Am. Chem. Soc. 1956, 60, 151-156.
50. Patel, S.; Smith, A. J.; Chapman, K. L.; Fletcher, A. E.; Kemp, J. A.; Marshall, G. R.; Hargreaves, R. J.; Ryecroft, W.; Iversen, L. L.; Iversen, S. D.; Baker, R.; Showell, G. A.; Bourrain, S.; Neduvelil, J. G.; Matassa, V. G.; Freedman, S. B. Biological Properties of the Benzodiazepine Amidine Derivative L-740,093, a Cholecystokinin-B/Gastrin Receptor Antagonist with High Affinity In Vitro and High Potency In Vivo. Mol. Pharmacol. 1994, 46, 943-948.
51. Chen, I.-I.; Dorley, J. M.; Ramjit, H. G.; Pitzenberger, S. M.; Lin, J. H. Physiological Disposition and Metabolism of L-365,260, a Potent Antagonist of Brain Cholecystokinin Receptor, in Laboratory Animals. Drug Metab. Disp. 1992, 20, 390-395.
52. Smith, D. A.; Jones, B. C.; Walker, D. C. Design of Drugs Involving the Concepts and Theories of Drug Metabolism and Pharmacokinetics. Med. Res. Rev. 1996, 16, 243-266.
53. Sybyl 6.2; Tripos Inc, St. Louis, MO (htpp://www.tripos.com).
54. Treasurywala, A. M.; Jaeger, E. P.; Peterson, M. L. Conformational searching methods for small molecules. III. Study od stochastic methods available in SYBYL and MACROMODEL. J. Comput. Chem. 1996, 17, 1171-1182.
55. MOPAC 6, J. J. P. Stewart, QCPE Program 455.