Using deuterium in drug discovery: Leaving the label in the drug

Journal of Medicinal Chemistry

Volumn 57, Issue 9, 2014, Pages 3595-3611

  Gant, Thomas G ^a  

^a Recondite Falls Discovery LLC ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 BROMO 2,6 DIFLUOROBENZYLOXY) 5 [3 [4 (1 PYRROLIDINYL)BUTYL]UREIDO] 4 ISOTHIAZOLECARBOXAMIDE; ALANINE DERIVATIVE; BORTEZOMIB; CTP 347; CTP 499; CYTOCHROME P450 2A6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; DEUTERIUM; DNA; DRUG METABOLITE; HALOTHANE; HYDROGEN; ISOTOPE; NEW DRUG; NIFEDIPINE; PROTEIN TYROSINE KINASE INHIBITOR; REAGENT; RNA; TAMOXIFEN; UNCLASSIFIED DRUG; VENLAFAXINE;

ADVERSE OUTCOME; ARTICLE; BINDING AFFINITY; CHEMICAL REACTION; CRYSTALLOGRAPHY; DRUG APPROVAL; DRUG DOSAGE FORM COMPARISON; DRUG FORMULATION; DRUG HALF LIFE; DRUG INDUSTRY; DRUG MECHANISM; DRUG METABOLISM; DRUG RESEARCH; DRUG SAFETY; DRUG SOLUBILITY; DRUG STRUCTURE; ENZYME ACTIVITY; FOOD AND DRUG ADMINISTRATION; GENOTOXICITY; HUMAN; KINETICS; MASS SPECTROMETRY; NEUROPATHIC PAIN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXIDATION;

CARBON; DEUTERIUM; DRUG DISCOVERY; DRUG INDUSTRY; HYDROGEN BONDING; KINETICS; OXIDATION-REDUCTION;

EID: 84900296719     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4007998     Document Type: Article

References (72)

1. Foster, A. B. Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design Adv. Drug Res. 1985, 14, 1-40
2. Garland, W. A. The Use of Deuterated Analogs of Drugs as Medicinal Agents: Introduction and Report of Discussion. In Synthesis and Applications of Isotopically Labeled Compounds, Proceedings of the Second International Symposium, Kansas City, MO, U.S., September 3-6, 1985; Muccino, R. R., Ed.; Elsevier: Amsterdam, 1986; pp 283-284.
3. Kushner, D. J.; Baker, A. Dunstall Pharmacological Uses and Perspectives of Heavy Water and Deuterated Compounds Can. J. Physiol. Pharmacol. 1999, 77, 79-88
4. Browne, T. R. Stable Isotopes in Pharmaceutical Research and Development Synth. Appl. Isot. Labeled Compd. 2001, 7, 519-532
5. Harbeson, S. L.; Tung, R. D. Deuterium in Drug Discovery and Development Annu. Rep. Med. Chem. 2011, 46 (24) 403-417
6. Adams, J. The Proteasome: A Suitable Antineoplastic Target Nat. Rev. Cancer 2004, 4, 349-360
7. See, for example, the following: Jagannathan, S.; Forsyth, T. P.; Kettner, C. A. Synthesis of Boronic Acid Analogs of Alpha-Amino Acids by Introducing Side Chains as Electrophiles J. Org. Chem. 2001, 66 (19) 6375-6380
8. Beebe, J.; Jani, J. P.; Knauth, E.; Goodwin, P.; Higdon, C.; Rossi, A. M.; Emerson, E.; Finkelstein, M.; Floyd, E.; Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.; Kou, K.; Gant, T. G.; Noe, M. C.; Foster, B.; Rastinejad, F.; Marx, M. A.; Schaeffer, T.; Whalen, P. M.; Roberts, W. G. Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy Cancer Res. 2003, 63, 7301-7309
9. Robert, F.; Gautier, D.; Dubrulle, B. The Solar System D/H Ratio: Observations and Theories Space Sci. Rev. 2000, 92, 201-224
10. Delsemme, A. H. 1999 Kuiper Prize Lecture; Cometary Origin of the Biosphere Icarus 2000, 146, 313-325
11. Valentine, D. L. Isotopic Remembrance of Metabolism Past Proc. Natl. Acad. Sci. U.S.A. 2009, 106 (31) 12565-12566
12. Martin, G. J.; Martin, M. L. Climatic Significance of Isotope Ratios Phytochem. Rev. 2003, 2, 179-190
13. Tommos, C.; Babcock, G. T. Proton and Hydrogen Currents in Photosynthetic Water Oxidation Biochim. Biophys. Acta 2000, 1458, 199-219
14. More OFerrall, R. A. A Pictorial Representation of Zero Point Energy and Tunnelling Contributions to Primary Hydrogen Isotope Effects J. Phys. Org. Chem. 2010, 23 (7) 572-579
15. Westheimer, F. H. The Magnitude of the Primary Kinetic Isotope Effect for Compounds of Hydrogen and Deuterium Chem. Rev. 1961, 61 (3) 265-273
16. Krishtalik, L. I. The Mechanism of the Proton Transfer: An Outline Biochim. Biophys. Acta 2000, 1458, 6-27
17. Scheiner, S. Calculation of Isotope Effects from First Principles Biochim. Biophys. Acta 2000, 1458, 28-42
18. 450 catalytic cycle depicted is an alteration of a figure and text from the following: Wei, L.; Locuson, C. W.; Tracy, T. S. Polymorphic Variants of CYP2C9: Mechanisms Involved in Reduced Catalytic Activity Mol. Pharmacol. 2007, 72 (5) 1280-1288
19. Kwart, L. D.; Horgan, A. G.; Kwart, H. Structure of the Reaction Barrier in the Selenoxide-Mediated Formation of Olefins J. Am. Chem. Soc. 1981, 103, 1232-1234 and references therein
20. Ortiz de Montellano, P. R., Ed. Cytochrome P450: Structure, Mechanism, and Biochemistry, 3 rd ed.; Kluwer Academic/Plenum Publishers: New York, 2005.
21. Lee, J. S.; Obach, R. S.; Fischer, M. B. Drug Metabolism Enzymes; FontisMedia SA / Marcel Dekker Inc.: Lausanne, Switzerland / New York, NY, U.S., 2003.
22. Brzezinski, P. Proton-Transfer Reactions in Bioenergetics Biochim. Biophys. Acta 2000, 1458, 1-5 and subsequent articles in this special edition
23. Guengerich, F. P.; Parikh, A.; Yun, C.-H.; Kim, D.; Nakamura, K. What Makes P450s Work? Searches for Answers with Known and New P450s Drug Metab. Rev. 2000, 32 (3, 4) 267-281
24. 1H] Amino Acids into Fully Deuterated Algae Biochim. Biophys. Acta 1970, 200, 26-33
25. Busenlehner, L. S.; Armstrong, R. N. Insights into Enzyme Structure and Dynamics Elucidated by Amide H/D Exchange Mass Spectrometry Arch. Biochem. Biophys. 2005, 433, 34-46
26. Baldwin, R. M. Imaging MAO-A Levels by PET Using the Deuterium Isotope Effect J. Nucl. Med. 2005, 46 (9) 1411-1413
27. Schramm, V. L. Binding Isotope Effects: Boon and Bane Curr. Opin. Chem. Biol. 2007, 11, 529-536
28. Scheppele, S. E. Kinetic Isotope Effects as a Valid Measure of Structure-Reactivity Relationships. Isotope Effects and Nonclassical Theory Chem. Rev. 1972, 72 (5) 511-532
29. Cleland, W. W. The Use of Isotope Effects to Determine Enzyme Mechanisms Arch. Biochem. Biophys. 2005, 433, 2-12
30. Basran, J.; Sutcliffe, M. J.; Scrutton, N. S. Deuterium Isotope Effects during Carbon-Hydrogen Bond Cleavage by Trimethylamine Dehydrogenase J. Biol. Chem. 2001, 276 (27) 24581-24587
31. Although Dr. Urey won the Nobel Prize in 1934 for his discovery, he became better known to most for his pioneering work on the creation of lifes building blocks from artificial primordial conditions, the Miller-Urey experiment, as well as his work on developing the atomic bomb (requiring isotopic purification). See the following: Miller, S. L.; Urey, H. C. Organic Compound Synthesis on the Primitive Earth Science 1959, 130 (3370) 245-251
32. Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The Renaissance of H/D Exchange Angew. Chem., Int. Ed. 2007, 46, 7744-7765
33. 2O Org. Lett. 2004, 6 (9) 1485-1487
34. Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota, K. Aromatic Ring Favorable and Efficient H-D Exchange Reaction Catalyzed by Pt/C Tetrahedron Lett. 2005, 46, 6995-6998
35. 2H]Phenylacetic Acid in High Enantiomeric Excess J. Chem. Soc, Chem. Commun. 2000, 1519-1520
36. 2H Patterns in Natural Compounds and Its Importance for the Elucidation of Biosynthetic Pathways Phytochem. Rev. 2003, 2, 61-85
37. 2H NMR: An Approach to Understanding Metabolism and Enzyme Mechanism? Phytochem. Rev. 2003, 2, 87-102
38. 4 J. Chem. Phys. 1965, 42, 2683-2686
39. Nelson, S. D.; Trager, W. F. The Use of Deuterium Isotope Effects To Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity Drug Metab. Dispos. 2003, 31 (12) 1481-1497
40. McCarty, L. P. US 4,069, 346, 1978; Dow Chemical Company.
41. 2H-3-Fluoro- d -alanine Drug Metab. Dispos. 1986, 14 (6) 668-673 and references cited therein
42. Rosenbaum, J. F.; Fava, M.; Hoog, S. L.; Ascroft, R. C.; Krebs, W. B. Selective Serotonin Reuptake Inhibitor Syndrome: A Randomized Clinical Trial Biol. Psychiatry 1998, 44 (2) 77-87
43. Knowles, S. R.; Shapiro, L. E.; Shear, N. H. Reactive Metabolites and Adverse Drug Reactions: Clinical Considerations Clin. Rev. Allergy Immunol. 2003, 24, 229-238
44. Hodgson, J. ADMET - Turning Chemicals into Drugs Nat. Biotechnol. 2001, 19, 722-726
45. Josephy, P. D.; Mannervik, B. Molecular Toxicology, 2 nd ed.; Oxford University Press: Oxford, U.K., 2006.
46. Muccino, R. R., Ed. Synthesis and Applications of Isotopically Labeled Compounds, Proceedings of the Second International Symposium, Kansas City, MO, U.S., September 3-6, 1985; Elsevier: Amsterdam, 1986; p 283. Session Chairman: W. A. Garland.
47. Foster, R. T.; Lewanczuk, R.; Caille, G. US 5,846,514, 1998; abandoned.
48. Uttamsingh, V.; Wells, D.; Soergel, D. CTP-347, a Deuterated Paroxetine Analog Exhibits Reduced Mechanism-Based Inactivation of CYP2D6 in Healthy Women. Presented at the 38th American College of Clinical Pharmacology, 2009.
49. Sabounjian, L.; Shipley, J.; Braman, V.; Harnett, M.; Wu, L.; Turnquist, D.; Graham, P. Design and Rationale for Randomized, Double-Blind, Placebo-Controlled Phase 2 Study To Evaluate the Safety and Efficacy of CTP-499 in Patients with Diabetic Nephropathy (DN) Adv. Chronic Kidney Dis. 2012, 19 (2) 123 (poster abstract)
50. Concert Pharmaceuticals Presents Preclinical Results Demonstrating CTP-499, a Novel Treatment for Diabetic Kidney Disease, Ameliorated Renal Fibrosis and Inflammation in Vivo. www.concertpharma.com/kidneyweek2012.htm (Nov 1, 2012).
51. Braman, V.; Graham, P.; Cheng, C.; Turnquist, D.; Harnett, M.; Sabounjian, L.; Shipley, J. A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy Clin. Pharmacol. Drug Dev. 2013, 2 (1) 53-66
52. A Phase 2 Study To Evaluate the Safety and Efficacy of CTP-499 in Type 2 Diabetic Nephropathy Patients. http://www.clinicaltrials.gov/ct2/show/ NCT01487109?term=ctp-499&rank=3.
53. Gant, T. G.; Sarshar, S. Methods of Reduction of Interpatient Variability. US 2010/0076087 A1, March 25, 2010.
54. Benowitz, N. L.; Perez-Stable, E. J.; Fong, I.; Modin, G.; Herrera, B.; Jacob, P., III. Ethnic Differences in N-Glucuronidation of Nicotine and Cotinine J. Pharmacol. Exp. Ther. 1999, 291 (3) 1196-1203
55. Malmstrom, K.; Daniels, S.; Kotey, P.; Seidenberg, B. C.; Desjardins, P. J. Comparison of Rofecoxib and Celecoxib, Two Cyclo-Oxygenase-2 Inhibitors, in Postoperative Dental Pain: A Randomized, Placebo- and Active-Comparator Controlled Clinical Trial Clin. Ther. 1999, 21 (10) 1653-1663
56. Mukherjee, D.; Nissen, S. E.; Topol, E. J. Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors JAMA, J. Am. Med. Assoc. 2001, 286 (8) 954-959
57. 5-Ethyl]-tamoxifen Implicates ?-Hydroxylation of the Ethyl Group as a Major Pathway of Tamoxifen Activation to a Liver Carcinogen Carcinogenesis 1994, 15 (8) 1487-1492
58. 5-Ethyl] Tamoxifen Carcinogenesis 1995, 16 (4) 683-688
59. 4502B6 and Identification of the Modified Residue on the Apoprotein Drug Metab. Dispos. 2012, 40 (12) 2280-2288
60. Roffey, S. J.; Obach, R. S.; Gedge, J. I.; Smith, D. A. What Is the Objective of the Mass Balance Study? A Retrospective Analysis of Data in Animal and Human Excretion Studies Employing Radiolabeled Drugs Drug Metab. Rev. 2007, 39, 17-43
61. 2O in Mammals Ann. N.Y. Acad. Sci. 1960, 84, 736-744
62. Schoeller, D. A. Measurement of Energy Expenditure in Free-Living Humans by Using Doubly Labeled Water J. Nutr. 1988, 118, 1278-1289
63. Dufner, D.; Previs, S. Measuring in Vivo Metabolism Using Heavy Water Curr. Opin Clin. Nutr. Metab. Care 2003, 6, 511-517
64. Blake, M. I.; Crespi, H. L.; Mohan, V.; Katz, J. J. Isolation of Fully Deuterated Metabolites from Scenedesmus obliquus Grown in Deuterium Oxide J. Pharm. Sci. 1961, 50 (5) 425-429
65. 2O Biotechnol. Bioeng. 1971, 13, 779-793
66. Siegel, B. V.; Lund, R. O.; Wellings, S. R.; Bostic, W. L. Growth of HeLa Cells in Heavy Water Exp. Cell Res. 1960, 19, 187-189
67. Crespi, H. L.; Archer, S. M.; Katz, J. J. The Culture of Algae and Other Micro-Organisms in Deuterium Oxide Nature 1959, 184, 729-730
68. Strain, H. H.; Thomas, M. R.; Crespi, H. L.; Blake, M. I.; Katz, J. J. Chloroplast Pigments and Photosynthesis in Deuterated Green Algae Ann. N.Y. Acad. Sci. 1960, 84, 617-633
69. Flaumenhaft, E.; Conrad, S. M.; Katz, J. J. Cytochemical Studies on Deuterated Green Algae Ann. N.Y. Acad. Sci. 1960, 84, 634-643
70. Itoh, M. K.; Inoshita, K.; Titanic, T. The Effect of Dilute Heavy Water on Tuberculosis bacillus Bull. Chem. Soc. Jpn. 1935, 10, 260
71. Swain, C. G.; Stivers, E. C.; Reuwer, J. F., Jr.; Schaad, L. J. Use of Hydrogen Isotope Effects To Identify the Attacking Nucleophile in the Enolization of Ketones Catalyzed by Acetic Acid J. Am. Chem. Soc. 1958, 80 (21) 5885-5893
72. Urey, H. C. In Encyclopaedia Britannica, 14 th ed.; Encyclopaedia Britannica, Inc.: Chicago, IL, 1936.