Medicinal chemistry and applications of incretins and DPP-4 inhibitors in the treatment of type 2 diabetes mellitus

Open Medicinal Chemistry Journal

Volumn 5, Issue SPEC. ISSUE 2, 2011, Pages 82-92

  Lotfy, Mohamed ^a   Singh, Jaipaul ^b   Kalász, Huba ^c   Tekes, Kornelia ^c   Adeghate, Ernest ^d  

^a Faculty of Science   (United Arab Emirates)

^b UNIVERSITY OF CENTRAL LANCASHIRE   (United Kingdom)

^c SEMMELWEIS UNIVERSITY   (Hungary)

^d UNITED ARAB EMIRATES UNIVERSITY   (United Arab Emirates)

Author keywords

DPP 4 inhibitors; Incretins; Medicinal chemistry; Type 2 diabetes

Indexed keywords

ADENOVIRUS VECTOR; ALBIGLUTIDE; ALOGLIPTIN; DENAGLIPTIN; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; DUTOGLIPTIN; EXENDIN 4; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INCRETIN; ISOLEUCINE THIAZOLIDIDE; LINAGLIPTIN; LIRAGLUTIDE; METFORMIN; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SULFONYLUREA; TASPOGLUTIDE; VILDAGLIPTIN;

CONSTIPATION; CORONARY ARTERY DISEASE; DEEP VEIN THROMBOSIS; DIABETES MELLITUS; DIZZINESS; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG OVERDOSE; DRUG STRUCTURE; ENZYME DEGRADATION; ENZYME INHIBITION; GASTROINTESTINAL SYMPTOM; GENE TRANSFER; GLUCOSE BLOOD LEVEL; HUMAN; HYPOGLYCEMIA; INJECTION SITE RASH; INSULIN RELEASE; LEUKOPENIA; MAXIMUM PLASMA CONCENTRATION; MYALGIA; NAUSEA; NEPHROLITHIASIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREATITIS; PHARYNGITIS; PRIORITY JOURNAL; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SKIN DEFECT; TIME TO MAXIMUM PLASMA CONCENTRATION; UNSPECIFIED SIDE EFFECT; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; UVEITIS; VIRAL GENE THERAPY; WEIGHT GAIN;

EID: 80455131061     PISSN: None     EISSN: 18741045     Source Type: Journal    
DOI: 10.2174/1874104501105010082     Document Type: Review

References (124)

1. D'Souza, A.; Hussain, M.; Howarth, F.C.; Woods, N.M.; Bidasee, K.; Singh, J. Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart. Mol. Cell Biochem., 2009, 331, 89-116.
2. Kumar, P.J.; Clark, M. Diabetes mellitus and other disorders of metabolism. In: Kumar PJ, Clark M (eds) Textbook of Medicine. Saunders, London, 2006, 1069-1122.
3. Havale, S.H.; Pal, M. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem., 2009, 17, 1783-1802.
4. Amos, A.; McCarty, D.; Zimmet, P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet. Med., 1997, 14, S1-S85.
5. Zimmet, P.Z.; Alberti, K.G. Globalisation and the noncommunicable disease epidemic. Obesity, 2006, 14, 1-3.
6. World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications; Part 1. Diagnosis and Classification of Diabetes Mellitus. Geneva: Department of Non-communicable Disease Surveillance, WHO; 1999.
7. King, H.; Aubert, R.; Herman, W. Global burden of diabetes, 1995-2025. Prevalence, numerical estimates and projections. Diabetes Care, 1998, 21, 1414-1431.
8. Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 2003, 51, 102-10.
9. Karaca, M.; Magnan, C.; Kargar, C. Functional pancreatic beta-cell mass: Involvement in type 2 diabetes and therapeutic intervention. Diabetes Metab., 2009, 35, 77-84.
10. McIntyre, N.; Holdsworth, C.D.; Turner, D.S. New interpretation of oral glucose tolerance. Lancet, 1964, 2, 20-21.
11. Labarre, J. Sur les possibilities d'un traitement due diabete parl'incretine. Bull. Acad. R. Med. Belg. 1932, 12, 620-634.
12. Creutzfeldt, W.; Ebert, R. New developments in the incretin concept. Diabetologia, 1985, 28, 565-573.
13. Pederson, R.A.; Brown, J.C. The insulinotropic action of gastric inhibitory polypeptide in the perfused isolated rat pancreas. Endocrinology, 1976, 99, 780-785.
14. Ross, S.A.; Dupre, J. Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects. Diabetes, 1978, 27, 327-333.
15. Kieffer, T.J.; Habener, J.F. The glucagon-like peptides. Endocr. Rev., 1999, 20, 876-913.
16. Wideman, R.D.; Kieffer, T.J. Glucose-dependent insulinotropic polypeptide as a regulator of beta cell function and fate. Horm. Metab. Res., 2004, 36, 782-786.
17. Nikolaidis, L.A.; Elahi, D.; Shen, Y.; Shannon, R.P. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H2401-H2408.
18. Ban, K.; Noyan-Ashraf, M.H.; Hoefer, J.; Bolz, S.S.; Drucker, D.J.; Husain, M. Cardioprotective and vasodilatory actions of glucagonlike peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation, 2008, 117, 2340-2350.
19. Sokos, G.G.; Bolukoglu, H; German, J.; Hentosz, T.; Magovern, G.J.; Maher, T.D.; Dean, D.A.; Bailey, S.H.; Marrone, G.; Benckart, D.H.; Elahi, D.; Shannon, R.P. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am. J. Cardiol. 2007, 100, 824-829.
20. Sonne, D.P.; Engstrom, T.; Treiman, M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemiareperfusion injury in rat heart. Regul. Pept., 2008, 146, 243-249.
21. Ding, K.H.; Zhong, Q.; Xie, D.; Chen, H.X.; Della-Fera, M.A.; Bollag, R.J.; Bollag, W.B.; Gujral, R.; Kang, B.; Sridhar, S.; Baile, C.; Curl, W.; Isales, C.M. Impact of glucose-dependent insulinotropic peptide on age-induced bone loss. J. Bone Miner. Res., 2008, 23, 536-543.
22. Xie, D.; Zhong, Q.; Ding, K.H.; Cheng, H.; Williams, S.; Correa, D.; Bollag, W.B.; Bollag, R.J.; Insogna, K.; Troiano, N.; Coady, C.; Hamrick, M.; Isales, C.M. Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone, 2007, 40, 1352-1360.
23. Meier, J.J.; Gallwitz, B.; Siepmann, N.; Holst, J.J.; Deacon, C.F.; Schmidt, W.E.; Nauck, M.A. Gastric inhibitory polypeptide (GIP) dosedependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia, 2003, 46, 798-801.
24. Baggio, L.L.; Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology, 2007, 132, 2131-2157.
25. Gautier, J.F.; Choukem, S.P.; Girard, J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab., 2008, 34 (Suppl 2), S65-S72.
26. Hansen, L.; Deacon, C.F.; Orskov, C.; Holst, J.J. Glucagon-like peptide-1-(7-36) amide is transformed to glucagon-like peptide-1- (9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology, 1999, 140, 5356-5363.
27. Deacon, C.F.; Johnsen, A.H.; Holst, J.J. Degradation of glucagonlike peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J. Clin. Endocrinol. Metab., 1995, 80, 952-957.
28. Mentlein, R. Dipeptidyl-peptidase IV (CD26) - role in the inactivation of regulatory peptides. Regul. Pept., 1999, 85, 9-24.
29. Green, B.D.; Flatt, P.R. Incretin hormone mimetics and analogues in diabetes therapeutics. Best Pract. Res. Clin. Endocrinol. Metab., 2007, 21, 497-516.
30. Eng, J.; Kleinman, W.A.; Singh, L.; Singh, G.; Raufman, J.P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem., 1992, 267, 7402-7405.
31. Barnett, A. Exenatide. Expert Opin. Pharmacother., 2007, 8, 2593-2608.
32. Xu, G.; Stoffers, D.A.; Habener, J.F.; Bonner-Weir, S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes, 1999, 48, 2270-2276.
33. Tourrel, C.; Bailbe, D.; Meile, M.J.; Kergoat, M.; Portha, B. Glucagon- like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes, 2001, 50, 1562-1570.
34. Tourrel, C.; Bailbe, D.; Lacorne, M.; Meile, M.J.; Kergoat, M.; Portha, B. Persistent improvement of type 2 diabetes in the Goto- Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes, 2002, 51, 1443-1452.
35. Stoffers, D. A.; Desai, B.M.; DeLeon, D.D.; Simmons, R.A. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes, 2003, 52, 734-740.
36. Gedulin, B.R.; Nikoulina, S.E.; Smith, P.A.; Gedulin, G.; Nielsen, L.L.; Baron, A.D.; Parkes, D.G.; Young, A. Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulinresistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology, 2005, 146, 2069-2076.
37. Degn, K.B.; Juhl, C.B.; Sturis, J.; Jakobsen, G.; Brock, B.; Chandramouli, V.; Rungby, J; Landau, B.R.; Schmitz, O. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes, 2004, 53, 1187-1194.
38. Juhl, C.B.; Hollingdal, M.; Sturis, J.; Jakobsen, G.; Agerso, H.; Veldhuis, J.; Porksen, N.; Schmitz, O. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes, 2002, 51, 424-429.
39. Sturis, J.; Gotfredsen, C.F.; Romer, J.; Rolin, B.; Ribel, U.; Brand, C.L.; Wilken, M.; Wassermann, K.; Deacon, C.F.; Carr, R.D.; Knudsen, L.B. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. Br. J. Pharmacol., 2003, 140, 123-132.
40. Bregenholt, S.; Moldrup, A.; Blume, N.; Karlsen, A.E.; Nissen, F.B.; Tornhave, D.; Knudsen, L.B.; Petersen, J.S. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem. Biophys. Res. Commun., 2005, 330, 577-584.
41. Wajchenberg, B.L. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev., 2007, 28, 187-218.
42. Tracy, M.A.; Ward, K.L.; Firouzabadian, L.; Wang, Y.; Dong, N.; Qian, R.; Zhang, Y. Factors affecting the degradation rate of poly(lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials, 1999, 20, 1057-1062.
43. Drucker, D.J.; Buse, J.B.; Taylor, K.; Kendall, D.M.; Trautmann, M.; Zhuang, D.; Porter, L. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet, 2008, 372, 1240-1250.
44. Kim, D.; MacConell, L.; Zhuang, D.; Kothare, P.A.; Trautmann, M.; Fineman, M.; Taylor K. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care, 2007, 30, 1487-1493.
45. Nauck, M.A.; Ratner, R.E.; Kapitza, C.; Berria, R.; Boldrin, M.; Balena, R. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care, 2009, 32, 1237-1243.
46. Tomkin, G.H. Albiglutide, an albumin-based fusion of glucagonlike peptide 1 for the potential treatment of type 2 diabetes. Curr. Opin. Mol. Ther., 2009, 11, 579-588.
47. Matthews, J.E.; Stewart, M.W.; De Boever, E.H.; Dobbins, R.L.; Hodge, R.J.; Walker, S.E.; Holland, M.C.; Bush, M.A. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J. Clin. Endocrinol. Metab., 2008, 93, 4810-4817.
48. Bush, M.A.; Matthews, J.E.; De Boever, E.H.; Dobbins, R.L.; Hodge, R.J.; Walker, S.E.; Holland, M.C.; Gutierrez, M.; Stewart, M.W. Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes. Metab., 2009, 11, 498-505.
49. Baggio, L.L.; Huang, Q.L.; Brown, T.J.; Drucker, D.J. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes, 2004, 53, 2492-2500.
50. Liu, M.J.; Shin, S.; Li, N.; Shigihara, T.; Lee, Y.S.; Yoon, J.W.; Jun, H.S. Prolonged remission of diabetes by regeneration of beta cells in diabetic mice treated with recombinant adenoviral vector expressing glucagon-like peptide-1. Mol. Ther., 2007, 15, 86-93.
51. Kumar, M.; Hunag, Y.; Glinka, Y.; Prud'Homme, G.J.; Wang, Q. Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice. Gene Ther., 2007, 14, 162-172.
52. Deacon, C.F.; Nauck, M.A.; Meier, J.; Hücking, K.; Holst, J.J. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J. Clin. Endocrinol. Metab., 2000, 85, 3575-3581.
53. Deacon, C.F. Circulation and degradation of GIP and GLP-1. Hormone Metab. Res., 2004, 36, 761-765.
54. Lambeir, A.M.; Durinx, C.; Scharpe, S.; and De Meester, I. Dipeptidylpeptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPPIV. Crit. Rev. Clin. Lab. Sci., 2003, 40, 209-294.
55. Abbott, C.A.; Baker, E.; Sutherland, G.R.; Mc Caughan, G.W. Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics., 1994, 40, 331-338.
56. Pratley, R.E.; Gilbert, M. Targeting incretins in type 2 diabetes: Role of GLP-1 receptor agonists and DPP-4 inhibitors. Rev. Diabet. Stud., 2008, 5, 73-94.
57. Pratley, R.E. Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes. Medscape J. Med.; 2008, 10, 171.
58. Ahren, B.; Landin-Olsson, M.; Jansson, P.A.; Svensson, M.; Holmes, D. Schweizer, A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduces glucagon levels in type 2 diabetes. J. Clin. Endocrino. Metab., 2004, 89, 2078-2084.
59. Mari, A.; Sallas, W.M.; He, Y.L.; Watson, C.; Ligueros-Saylan, M.; Dunning, B.E.; Deacon, C.F.; Holst, J.J.; Foley, J.E. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves modelassessed beta-cell function in patients with type 2 diabetes. J. Clin. Endocrino. Metab., 2005, 90, 4888-4894.
60. Ahren, B.; Pacini, G.; Foley, J.E.; Schweizer, A. Improved mealrelated beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care, 2005, 28, 1936-1940.
61. Raz, I.; Hanefeld, M.; Xu, L.; Caria, C.; Williams-Herman, D.; Khatami, H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia, 2006, 49, 2564-2571.
62. Ahren, B.; Pacini, G.; Tura, A.; Foley, J.E.; Schweizer, A. Improved meal-related insulin processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. Hormone Metab. Res., 2007, 39, 826-829.
63. Ahren, B.; Simonsson, E.; Larsson, H.; Landin-Olsson, M.; Torgeirsson, H.; Jansson, P.A.; Sandqvist, M.; Båvenholm, P.; Efendic, S.; Eriksson, J.W.; Dickinson, S.; Holmes, D. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4 week study period in type 2 diabetes. Diabetes Care, 2002, 25, 869-875.
64. Brazg, R.; Xu, L.; Dalla Man, C.; Cobelli, C.; Thomas, K.; Stein, P.P. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes. Metab., 2007, 9, 186-193.
65. Ahren, B. Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin - diabetes control and potential dverse events. Best Pract. Res. Clin. Endocrinol. Metab., 2009, 23, 487-498.
66. Ahren, B. DPP-4 inhibitors. Best Pract. Res. Clin. Endocrinol. Metab., 2007, 21, 517-533.
67. Ahren, B. Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications. Diabetes Care, 2007, 30, 1344-1350.
68. Karasik, A.; Aschner, P.; Katzeff, H.; Davies, M.J.; Stein, P.P. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr. Med. Res. Opinion, 2008, 24, 489-496.
69. Ahren, B. Vildagliptin: novel pharmacological approach to treat type 2 diabetes. Therapy, 2008, 5, 79-90.
70. Augeri, D.J.; Robl, J.A.; Betebenner, D.A. Magnin, D.R.; Khanna, A.; Robertson, J.G.; Wang, A.; Simpkins, L.M.; Taunk, P.; Huang, Q.; Han, S.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G.E.; Egan, D.M.; Marcinkeviciene, J.; Chang, S.Y.; Biller, S.A.; Kirby, M.S.; Parker, R.A.; Hamann L.G. Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent longacting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2006, 48, 5025-5037.
71. Bergman, A.J.; Cote, J.; Yi, B.; Marbury, T.; Swan, S.K.; Gottesdiener, K.; Wagner, J.; Herman, G.A. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care, 2007, 30, 1862-1864.
72. Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M.H.; He, H.; Hickey, G.J.; Kowalchick, J.E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M.E.; Patel, R.A.; Petrov, A.; Scapin, G.; Patel, S.B.; Roy, R.S.; Wu, J.K.; Wyvratt, M.J.; Zhang, B.B.; Zhu, L.; Thornberry, N.A.; Weber, A.E. (2R)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro[1, 2, 4]triazolo[4, 3-a]pyrazin-7(8H)-yl]-1-(2, 4, 5- trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2005, 48, 141-151.
73. Aschner, P.; Kipnes, M.S.; Lunceford, J.K.; Sanchez, M.; Mickel, C.; Williams-Herman, D.E. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care, 2006, 29, 2632-2637.
74. Charbonnel, B.; Karasik, A.; Liu, J.; Wu, M.; Meininger, G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabe tes inadequately controlled with metformin alone. Diabetes Care, 2006, 29, 2638-2643.
75. Karasik, A.; Charbonnell, B.; Liu, J.; Wu, M.; Meehan, A.; Meininger, G. Sitagliptin added to ongoing metformin therapy enhanced glycemic control and beta-cell function in patients with type 2 diabetes. Diabetes, 2006, 55(suppl 1), 119-120 (Abstr 501-P).
76. Rosenstock, J.; Brazg, R.; Andryuk, P.J.; McCrary S.C.; Lu, K.; Stein, P. Addition of sitagliptin to pioglitazone improved glycemic control with neutral weight effect over 24 weeks in inadequately controlled type 2 diabetes (T2DM). Diabetes, 2006, 55 (Suppl 1), 132-133 (Abstr 556-P).
77. Xu, L.; Williams-Herman, D.E. Initial combination therapy with sitagliptin, a selective DPP-4 inhibitor, and metformin leads to marked improvement in β cell function in patients with type 2 diabetes. Diabetologia, 2007, 50, (Suppl.) Abstract # 884.
78. Migoya, E.M.; Miller, J.; Larson, P.; Tanes, M.; Hilliard, D.; Deacon, C.; Guitierrez, M.; Stoch, A.; Herman, G.A.; Stein, P.P.; Holst, J.J.; Wagner, J.A. Sitagliptin, a selective DPP-4 inhibitor, and metformin have complementary effects to increase active GLP-1 concentrations. Diabetes, 2007, 56, A74 (Abstract).
79. Herman, G.A.; Bergman, A.; Stevens, C.; Kotey, P.; Yi, B.; Zhao, P.; Dietrich, B.; Golor, G.; Schrodter, A.; Lasseter, K.C.; Kipnes, M.S.; Snyder, K.; Hilliard, D.; Tanen, M.; Cilissen, C.; De Smet, M.; De Lepeleire, I.; Van Dyck, K.; Wang, A.Q.; Zeng, W.; Davies, M.J.; Tanaka, W.; Holst, J.J.; Deacon, C.F.; Gottesdiener, K.M.; Wagner, J.A. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J. Clin. Endocrinol. Metab., 2006, 91, 4612-4619.
80. Mu, J.; Woods, J.; Zhou, Y.P.; Roy, R.S.; Li, Z.; Zycband, E.; Feng, Y.; Zhu, L.; Li, C.; Howard, A.D.; Moller, D.E.; Thornberry, N.A.; Zhang, B.B. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes, 2006, 55, 1695-1704.
81. Villhauer, E.B.; Brinkman, J.A.; Naderi, G.B.; Burkey, B.F.; Dunning, B.E.; Prasad, K.; Mangold, B.L.; Russell, M.E.; Hughes, T.E.1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)- pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem., 2003, 46, 2774-2789.
82. El-Ouaghlidi, A.; Rehring, E.; Schweizer, A.; Holmes, D.; Nauck, M.A. The dipeptidyl peptidase IV inhibitor LAF237 does not accentuate reactive hypoglyaemia caused by the sulfonylurea glibenclamide administered before an oral glucose load in healthy subjects. Diabetes, 2003, 52 (Suppl 1), 118 (Abstr 507-P).
83. Rosenstock, J.; Baron, M.A.; Camisasca, R.P.; Cressier, F.; Couturier, A.; Dejager, S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes. Metab., 2007, 9, 175-185.
84. Garber, A.; Camisasca, R.P.; Ehrsam, E.; Collober-Maugeais, C.; Rochotte, E.; Lebeaut, A. Vildagliptin added to metformin improves glycemic control and may mitigate metformin-induced GI side effects in patients with type 2 diabetes (T2DM). Diabetes, 2006, 55(Suppl 1), 29 (Abstr 121-OR).
85. Pratley, R.E.; Jauffret-Kamel, S.; Galbreath, E.; Holmes, D. Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes. Horm. Metab. Res., 2006, 38, 423-428.
86. Rosenstock, J.; Baron, M.A.; Schweizer, A.; Mills, D.; Dejager, S. Vildagliptin is as effective as rosiglitazone in lowering HbA1c but withoutweight gain in drugnaive patients with type 2 diabetes (T2DM). Diabetes, 2006, 55(Suppl 1), 133 (Abstr 557-P).
87. Balas, B.; Baig, M.R.; Watson, C.; Dunning, B.E.; Ligueros- Saylan, M.; Wang, Y.; He, Y.L.; Darland, C.; Holst, J.J.; Deacon, C.F.; Cusi, K.; Mari, A.; Foley, J.E.; DeFronzo, R.A. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single dose administration in type 2 diabetic patients. J. Clin. Endocrinol. Metab., 2007, 92, 12249-12255.
88. Ahren, B.; Landin-Olsson, M.; Jansson, P.A.; Svensson, M.; Holmes, D.; Schweizer, A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J. Clin. Endocrinol. Metab., 2004, 89, 2078-2084.
89. Azuma, K.; Rádikovál, Z.; Mancino, J.; Toledo, F.G.S.; Thomas, E.; Kangani, C.; Man, C.D.; Cobelli, C.; Holst, J.J.; Deacon, C.F.; He, Y.L.; Ligueros-Saylan, M.; Serra, D.; Foley J.E.; Kelley, D.E. Measurements of islet function and glucose metabolism with the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. J. Clin. Endocrinol. Metab., 2008, 93, 459-464.
90. D'Alessio, D.A.; Tso, P. GLP-1 reduces intestinal lymph flow, triglyceride absorption and lipoprotein production in rats. Am. J. Physiol., 2005, 288, 6943-6949.
91. Tahrani, A.A., Milan, K. Piya, M.K. and Barnett, A.H. Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Adv. Ther., 2009, 26 (3): 249-262.
92. Kirby, M.S.; Dorso, C.; Wang, A.; Weigelt, C.; Kopcho, L.; Hamann, L.; Marcinkeviciene, J. In vitro enzymologic characteristics of saxagliptin, a highly potent and selective DPP4 inhibitor with"slow binding" characteristics. Clin. Chem. Lab. Med., 2008, 46, A29.
93. Rosenstock, J.; Sankoh, S.; List, J.F. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naïve patients with type 2 diabetes. Diabetes Obes. Metab., 2008, 10, 376-386.
94. Pratley, R.E.; Rosenstock, J.; Pi-Sunyer, F.X.; Banerji, M.A.; Schweizer, A.; Couturier, A.; Dejager, S. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care, 2007, 30, 3017-3022.
95. Rosenstock, J.; List, J.; Sankoh, S.; Chen, R. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naïve subjects with type 2 diabetes: results from a phase 2 dose-ranging study. Presented at: 43rd annual meeting of the European Society for the Study of Diabetes, 2007, September 17-21; Amsterdam, Netherlands. Abstract.
96. Defronzo, R.A.; Hissa, M.; Blauwet, M.B.; Chen, R.S. Saxagliptin added to metformin improves glycemic control in patients with type 2 diabetes. Presented at: 67th Scientific Sessions of the American Diabetes Association; June 22-26, 2007; Chicago, IL.2007, Abstract 0285-OR.
97. Demuth, H.U.; McIntosh, C.H.; Pederson, R.A. Type 2 diabetes- therapy with dipeptidyl peptidase IV inhibitors, Biochim. Biophys Acta, 2005, 1751, 33-44.
98. Lee, B.; Shi, L.; Kassel, D.B.; Asakawa, T.; Takeuchi, K.; Christopher, R.J. Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys. Eur. J. Pharmacol., 2008, 28, 306-314.
99. Fleck, P.; Mekki, Q.; Kipnes, M.; Wilson, C.; Pratley, R. Efficacy and safety of alogliptin and glyburide combination therapy in patients with type 2 diabetes. Diabetologia, 2008, 51(Suppl.), S37.
100. Pospisilik, J.A.; Martin, J.; Doty, T.; Ehses, J.A.; Pamir, N.; Lynn, F.C.; Piteau, S.; Demuth, H.U.; McIntosh, C.H.; Pederson, R.A. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin induced diabetic rats. Diabetes, 2003, 52, 741-750.
101. Thomas, L.; Himmelsbach, F.; Eckhardt, M.; Langkopf, E.; Mark, M. BI 1356, a novel and selective xanthine based DPP-IV inhibitor, exhibits a superior profile when compared to sitagliptin and vildagliptin. Diabetologia, 2007, 50, (Suppl.) Abstract # 879.
102. Dugi, K.A.; Heise, T.; Ring, A.; Graefe-Mody, U.; Ritzhaupt, A.; Huettner, S. BI 1356, a novel xanthine-based DPP-IV inhibitor, exhibits high potency with a wide therapeutic window and significantly reduces postprandial glucose excursions after an OGTT. Diabetologia, 2007, 50, (Suppl.) Abstract # 890.
103. H.P. PHX1149, a selective DPP4 inhibitor, improves postprandial blood glucose control in patients with type 2 diabetes. Diabetologia, 2007, 50, (Suppl.) Abstract #114.
104. Verspohl, E.J. Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol. Therapeut., 2009, 124, 113-138.
105. Pardossi-Piquard, R.; Dunys, J.; Yu, G.; St George-Hyslop, P.; Alves da Costa, C.; Checler, F. Neprilysin activity and expression are controlled by nicastrin. J. Neurochem., 2006, 97, 1052-1056.
106. Plamboeck, A.; Holst, J.J.; Carr, R.D.; Deacon, C.F. Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia, 2005, 48, 1882-1890.
107. Zander, M.; Madsbad, S.; Holst, J.J. GLP-1 for six weeks reduces body weight and improves insulin sensitivity and glycemic control in patients with Type 2 diabetes. Diabetes 2001, 50 (Suppl. 2), A31.
108. Gutzwiller, J-P., Drewe, J., Göke, B., Schmidt, H., Rohrer, B., Lareida, J., Beglinger, C., Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am. J. Physiol. 1999, 276, R1541-R1544
109. Holst, J.J., Ørskov, C., Vagn-Nielsen, O., Schwartz, T.W. Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987, 211, 169-174.
110. Nyenwe, E.A.; Jerkins, T.W.; Umpierrez, G.E.; Kitabchi, A.E. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011, 60, 1-23
111. Bjerre Knudsen, L.; Madsen, L.W.; Andersen, S.; Almholt, K.; de Boer, A.S.; Drucker, D.J.; Gotfredsen, C.; Egerod, F.L.; Hegelund, A.C.; Jacobsen, H.; Jacobsen, S.D.; Moses, A.C.; Mølck, A.M.; Nielsen, H.S.; Nowak, J.; Solberg, H.; Thi, T.D.; Zdravkovic, M. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010, 151, 1473-1486.
112. Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011, 96(3), 853-860.
113. Bosi, E.; Camisasca, R.P.; Collober, C.; Rochotte, E.; Garber, A.J. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care, 2007, 30, 890-895
114. Wesley, U.V.; McGroarty, M.; Homoyouni, A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res, 2005, 65, 1325-34
115. Olansky, L. Do incretin-based therapies cause acute pancreatitis? J Diabetes Sci Technol, 2010, 4, 228-229
116. Neumiller, J.J.; Campbell, R.K. Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Am J Health Syst Pharm, 2010, 67, 1515-25.
117. Anonymous. Saxagliptin. No more effective than other gliptins, but a high potential for drug interactions. Prescrire Int., 2011, 20, 33-37.
118. http://www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=100925&studyId=ED33C31C-01D3-4025-B568-910-D2FADDA37&compound=Denagliptin
119. Covington P, Christopher R, Davenport M, Fleck P, Mekki QA, Wann ER, Karim A: Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther, 2008, 30, 499-512.
120. Pederson, R.A.; White, H.A.; Schlenzig, D.; Pauly, R.P.; McIntosh, C.H.S.; Demuth, H.U. Improved Glucose Tolerance in Zucker Fatty Rats by Oral Administration of the Dipeptidyl Peptidase IV Inhibitor Isoleucine Thiazolidide. Diabetes 1998, 47, 1253-1258
121. Thornberry NA, Weber AE. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr Top Med Chem., 2007, 7, 557-568.
122. Forst, T.; Uhlig-Laske, B.; Ring, A.; Graefe-Mody, U.; Friedrich, C.; Herbach, K.; Woerle, H.-J; Dugi, K. A. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabetic Medicine, 2010, 27, 1409-1419.
123. Larsen MO, Rolin B, Ribel U, Wilken M, Deacon CF, Svendsen O, Gotfredsen CF, Carr RD. Valine pyrrolidide preserves intact glucose- dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass. Exp Diabesity Res., 2003, 4, 93-105.
124. Ahrén B, Hughes TE. Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrinreleasing peptide in mice. Endocrinology 2005, 146, 2055-2059.