The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption

Journal of Medicinal Chemistry

Volumn 52, Issue 14, 2009, Pages 4142-4148

  Huttunen, Kristiina M ^a   Mannila, Anne ^a   Laine, Krista ^a   Kemppainen, Eeva ^a   Leppanen, Jukka ^a   Vepsalainen, Jouko ^a   Jarvinen, Tomi ^a   Rautio, Jarkko ^a  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

BIGUANIDE DERIVATIVE; METFORMIN; N1,N1 DIMETHYL S CYCLOHEXYL N4 THIOHYDROXYLBIGUANIDINE; N1,N1 DIMETHYL S PHENYL N4 THIOHYDROXYLBIGUANIDINE; PRODRUG; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DIABETIC PATIENT; DISTRIBUTION VOLUME; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG POTENCY; DRUG SCREENING; DRUG STABILITY; DRUG SYNTHESIS; DRUG TRANSFORMATION; GASTROINTESTINAL SYMPTOM; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTESTINE ABSORPTION; LIPOPHILICITY; MALE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; QUANTITATIVE ANALYSIS; RAT;

ANIMALS; BIOLOGICAL AVAILABILITY; BUFFERS; DRUG DESIGN; HUMANS; HYDROGEN PEROXIDE; HYDROGEN-ION CONCENTRATION; HYDROPHOBICITY; INTESTINAL ABSORPTION; MALE; METFORMIN; OCTANOLS; PRODRUGS; RATS; RATS, WISTAR; SOLUTIONS; SULFAMERAZINE; WATER;

EID: 67650717860     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900274q     Document Type: Article

References (43)

1. Amos, A. F.; McCarty, D. J.; Zimmet, P. The Rising Global Burden of Diabetes and Its Complications: Estimates and Projections to the Year 2010. Diabetic Med. 1997, 5, S1-S85.
2. King, H.; Aubert, R. E.; Herman, W. H. Global Burden of Diabetes, 1995-2025: Prevalence, Numerical Estimates, and Projections. Diabetes Care 1998, 21, 1414-1431.
3. Skyler, J. S. Diabetes Mellitus: Pathogenesis and Treatment Strategies. J. Med. Chem. 2004, 47, 4113-4117.
4. Hogan, P.; Dall, T.; Plamen, N. Economic Costs of Diabetes in the U.S. in 2002. Diabetes Care 2003, 26, 917-932.
5. Zimmet, P.; Alberti, K. G.; Shaw, J. Global and Societal Implications of the Diabetes Epidemic. Nature 2001, 414, 782-787.
6. Davidson, M. B.; Peters, A. L. An Overview of Metformin in the Treatment of Type 2 Diabetes Mellitus. Am. J. Med. 1997, 102, 99-110.
7. Kirpichnikov, D.; McFarlane, S. I.; Sowers, J. R. Metformin: An Update. Ann. Intern. Med. 2002, 137, 25-33.
8. Strack, T. Metformin: A Review. Drugs Today 2008, 44, 303-314.
9. UK Prospective Diabetes Study (UKPDS 34) Group. Effect of Intensive Blood-Glucose Control with Metformin on Complications in Overweight Patients with Type 2 Diabetes (UKPDS 34). Lancet 1998, 352, 854-865.
10. Jackson, R. A.; Hawa, M. I.; Jaspan, J. B.; Sim, B. M.; Disilvio, L.; Featherbe, D.; Kurtz, A. B. Mechanism of Metformin Action in Non-Insulin-Dependent Diabetes. Diabetes 1987, 36, 632-640.
11. Klip, A.; Leiter, L. A. Cellular Mechanism of Action of Metformin. Diabetes Care 1990, 13, 696-704.
12. Wu, M.-S.; Johnston, P.; Sheu, W. H.-H.; Hollenbeck, C. B.; Jeng, C.-Y.; Goldfine, I. D.; Chen, Y.-D. I.; Reaven, G. M. Effect of Metformin on Carbohydrate and Lipoprotein Metabolism in NIDDM Patients. Diabetes Care 1990, 13, 1-8.
13. Bhalla, R. C.; Toth, K. F.; Tan, E.; Bhatty, R. A.; Mathias, E.; Sharma, R. V. Vascular Effects of Metformin. Possible Mechanisms for Its Antihypertensive Action in the Spontaneously Hypertensive Rat. Am. J. Hypertens. 1996, 9, 570-576.
14. Katakam, P. V.; Ujhelyi, M. R.; Hoenig, M.; Miller, A. W. Metformin Improves Vascular Function in Insulin-Resistant Rats. Hypertension 2000, 35, 108-112.
15. Montanari, G.; Bondioli, A.; Rizzato, G.; Puttini, M.; Tremoli, E.; Mussoni, L.; Mannucci, L.; Pazzucconi, F.; Sirtori, C. R. Treatment with Low Dose Metformin in Patients with Peripheral Vascular Disease. Pharmacol. Res. 1992, 25, 63-73.
16. Tucker, G. T.; Casey, C.; Phillips, P. J.; Connor, H.; Ward, J. D.; Woods, H. F. Metformin Kinetics in Healthy Subjects and in Patients with Diabetes Mellitus. Br. J. Clin. Pharmacol. 1981, 12, 235-246.
17. Dandona, P.; Fonseca, V.; Mier, A.; Beckett, A. G. Diarrhea and Metformin in a Diabetic Clinic. Diabetes Care 1983, 6, 472-474.
18. Krentz, A. J.; Ferner, R. E.; Bailey, C. J. Comparative Tolerability Profiles of Oral Antidiabetic Agents. Drug Saf. 1994, 11, 223-241.
19. Garber, A. J.; Duncan, T. G.; Goodman,A. M.; Mills, D. J.; Rohlf, J. L. Efficacy of Metformin in Type II Diabetes: Results of a Double-Blind, Placebo-Controlled, Dose-Response Trial. Am. J. Med. 1997, 103, 491-497.
20. Belcher, G.; Lambert, C.; Edwards, G.; Urquhart, R.; Matthews, D. R. Safety and Tolerability of Pioglitazone, Metformin, and Gliclazide in the Treatment of Type 2 Diabetes. Diabetes Res. Clin. Pract. 2005, 70, 53-62.
21. Cullen, E.; Liao, J.; Lukacsko, P.; Niecestro, R.; Friedhoff, L. Pharmacokinetics and Dose Proportionality of Extended-Release Metformin Following Administration of 1000, 1500, 2000 and 2500 mg in Healthy Volunteers. Biopharm. Drug Dispos. 2004, 25, 261-263.
22. Blonde, L.; Dailey, G. E.; Jabbour, S. A.; Reasner, C. A.; Mills, D. J. Gastrointestinal Tolerability of Extended-Release Metformin Tablets Compared to Immediate-Release Metformin Tablets: Results of a Retrospective Cohort Study. Curr. Med. Res. Opin. 2004, 20, 565-572.
23. Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. Lessons Learned from Marketed and Investigational Prodrugs. J. Med. Chem. 2004, 47, 2393-2404.
24. Stella, V. J.; Borchardt, R. T.; Hageman, M. J.; Oliyai, R.; Maag, H.; Tilley, J. Prodrugs: Challenges and Rewards (Parts 1 & 2); Springer Science: New York, 2007.
25. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Jarvinen, T.; Savolainen, J. Prodrugs: Design and Clinical Applications. Nat. Rev. Drug Discovert 2008, 7, 255-270.
26. Zhang, J.; Shi, Y.; Stein, P.; Atwal, K.; Li, C. One-Pot Synthesis of N,N′-Disubstituted Acylguanidines. Tetrahedron Lett. 2001, 43, 57-59.
27. Hernandez-Luis, F.; Hernandez-Campos, A.; Yepez-Mulia, L.; Cedillo, R.; Castillo, R. Synthesis and Hydrolytic Stability Studies of Albendazole Carrier Prodrugs. Bioorg. Med. Chem. Lett. 2001, 11, 1359-1362.
28. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990.
29. 1. Eur. J. Pharm. Sci. 1997, 5, 79-88.
30. Guan, J.; Zhang, Q.; Montip, G.; Karle, J. M.; Ditusa, C. A.; Milhous, W. K.; Skillman, D. R.; Lin, A. J. Structure Identification and Prophylactic Antimalarial Efficacy of 2-Guanidinoimidazolidinedione Derivatives. Bioorg. Med. Chem. 2005, 13, 699-704.
31. Greenhill, J. V.; Lue, P. Amidines and Guanidines in Medicinal Chemistry. Prog. Med. Chem. 1993, 30, 203-326.
32. Arafa, R. K.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson, W. D.; Stephens, C. E.; Boykin, D. W. Synthesis, DNA Affinity, and Antiprotozoal Activity of Fused Ring Dicationic Compounds and Their Prodrugs. J. Med. Chem. 2005, 48, 5480-5488.
33. Huttunen, K. M.; Leppanen, J.; Kemppainen, E.; Palonen, P.; Rautio, J.; Jarvinen, T.; Vepsalainen, J. Towards Metformin Prodrugs. Synthesis 2008, 22, 3619-3624.
34. Guarino, V. R.; Karunaratne, V.; Stella, V. J. Sulfenamides as Prodrugs of NH-Acidic Compounds: A New Prodrug Option for the Amide Bond. Bioorg. Med. Chem. Lett. 2007, 17, 4910-4913.
35. Hemenway, J. N.; Nti-Addae, K.; Guarino, V. R.; Stella, V. J. Preparation, Characterization and in Vivo Conversion of New Water-Soluble Sulfenamide Prodrugs of Carbamazepine. Bioorg. Med. Chem. Lett. 2007, 17, 6629-6632.
36. Di, L.; Kerns, E. H. Profiling Drug-like Properties in Discovery Research. Curr. Opin. Chem. Biol. 2003, 7, 402-408.
37. Dierickx, P. J. Formation of Reactive Oxygen Species in Rat Hepatoma-Derived Fa32 Cells To Predict Human Toxicity. Toxicol. in Vitro 2002, 16, 725-730.
38. Amrolia, P.; Sullivan, S. G.; Stern, A.; Munday, R. Toxicity of Aromatic Thiols in the Human Red Blood Cell. J. Appl. Toxicol. 1989, 9, 113-118.
39. Choi, Y. H.; Kim, S. G.; Lee, M. G. Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects. J. Pharm. Sci. 2006, 95, 2543-2552.
40. Proctor, W. R.; Bourdet, D. L.; Thakker, D. R. Mechanism Underlying Saturable Intestinal Absorption of Metformin. Drug Metab. Dispos. 2008, 36, 1650-1658.
41. Shu, Y.; Sheardown, A.; Brown, C.; Owen, R. P.; Zhang, S.; Castro, R. A.; Ianculescu, A. G.; Yue, L.; Lo, J. C.; Burchard, E. G.; Brett, C. M.; Giacomini, K. M. Effect of Genetic Variation in the Organic Transporter 1 (OCT1) on Metformin Action. J. Clin. Invest. 2007, 117, 1422-1431.
42. Shu, Y.; Brown, C.; Castro, R. A.; Shi, R. J.; Lin, E. T.; Owen, R. P.; Sheardown, A.; Yue, L.; Burchard, E. G.; Brett, C. M.; Giacomini, K. M. Effect of Genetic Variation in the Organic Cation Transporter 1, OCT1, on Metformin Pharmacokinetics. Clin. Pharmacol. Ther. 2008, 82, 273-280.
43. Waynforth, H. B.; Flecknell, P. A. Experimental and Surgical Technique in the Rat; Academic Press Ltd.: London, 1994.