Novel DPP-4 inhibitors against diabetes

Future Medicinal Chemistry

Volumn 6, Issue 7, 2014, Pages 793-808

  Liu, Yang ^a   Hu, Yongzhou ^a  

^a ZHEJIANG UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

ALOGLIPTIN; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; LINAGLIPTIN; POTASSIUM CHANNEL HERG; SAXAGLIPTIN; SITAGLIPTIN; TENELIGLIPTIN; VILDAGLIPTIN; [5 AMINO 4 (2,4,5 TRIFLUOROPHENYL) 1 CYCLOHEXENYL][5,6 DIHYDRO 3 (TRIFLUOROMETHYL) 1,2,4 TRIAZOLO[4,3 A]PYRAZIN 7(8H) YL]METHANONE; ANTIDIABETIC AGENT;

ANTIDIABETIC ACTIVITY; BINDING SITE; CLINICAL EVALUATION; COMBINATORIAL CHEMISTRY; CONFORMATION; CYCLIZATION; DIABETES MELLITUS; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG INDUSTRY; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; ENZYME STRUCTURE; GLUCOSE BLOOD LEVEL; HUMAN; HYPERGLYCEMIA; IC 50; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; PATIENT COMPLIANCE; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; STRUCTURE ACTIVITY RELATION; T LYMPHOCYTE ACTIVATION; WEIGHT GAIN; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; ENZYMOLOGY; METABOLISM;

ANIMALS; DIABETES MELLITUS; DIPEPTIDYL PEPTIDASE 4; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG DESIGN; DRUG STABILITY; HUMANS; HYPOGLYCEMIC AGENTS; MODELS, MOLECULAR;

EID: 84903170977     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.14.39     Document Type: Review

References (109)

1. World Health Organization. www.who.int/diabetes/facts/world-figures/en
2. International Diabetes Federation. Diabetes Atlas. www.eatlas.idf.org
3. Mizuno CS, Chittiboyina AG, Kurtz TW et al. Type 2 diabetes and oral antihyperglycemic drugs. Curr. Med. Chem. 15(1), 61-74 (2008
4. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin. Drug. Saf. 12(2), 153-175 (2013
5. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin. Invest. Drugs. 12(1), 87-100 (2003
6. Weber AE. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 47(17), 4135-4141 (2004
7. Deacon CF, Ahren B, Holst JJ. Inhibitors of dipeptidyl peptidase IV: A novel approach for the prevention and treatment of type 2 diabetes?. Expert Opin. Investig. Drugs. 13(9), 1091-1102 (2004
8. Demuth HU, McIntosh, CH, Pederson RA. Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors. Biochim. Biophys. Acta. 1751(1), 33-44 (2005
9. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int. J. Clin. Pract. 60(11), 1454-1470 (2006
10. Sebokova E, Christ AD, Boehringer M et al. Dipeptidyl peptidase IV inhibitors: The next generation of new promising therapies for the management of type 2 diabetes. Curr. Top. Med. Chem. 7(6), 547-555 (2007
11. Hunziker D, Hennig M, Peters JU. Inhibitors of dipeptidyl peptidase IV-recent advances and structural views. Curr. Top. Med. Chem. 5(16), 1623-1637 (2005
12. Gwaltney SL, Stafford JA. Inhibitors of dipeptidyl peptidase 4. Annu. Rep. Med. Chem. 40, 149-165 (2005
13. Wiedeman PE. DPPIV inhibition: Promising therapy for the treatment of type 2 diabetes. Prog. Med. Chem. 45, 63-109 (2007
14. Gwaltney SL. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase IV. Curr. Top. Med. Chem. 8(17), 1545-1552 (2008
15. Pei Z. From the bench to the bedside: Dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents. Curr. Opin. Drug Discov. Devel. 11(4), 512-532 (2008
16. Salvatore T, Carbonara O, Cozzolino D et al. Progress in the oral treatment of type 2 diabetes: Update on DPP-IV inhibitors. Curr. Diabetes Rev. 5(2), 92-101 (2009
17. Havale SH, Pal M. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem. 17(5), 1783-1802 (2009
18. Gupta R, Walunj SS, Tokala RK et al. Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of Type 2 diabetes. Curr. Drug Targets 10(1), 71-87 (2009
19. Weber AE, Thornberry NA. Dipeptidyl peptidase 4 inhibitors. In: Burger's Medicinal Chemistry, Drug Discovery, and Development (Seventh Edition). Wiley & Sons. NY, USA, 1-38 (2010
20. Chen SJ, Jiaang WT. Current advances and therapeutic potential of agents targeting dipeptidyl peptidases-IV,-II, 8/9 and fibroblast activation protein. Curr. Top. Med. Chem. 11(12), 1447-1463 (2011
21. Liu Y, Hu Y, Liu T. Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: Medicinal chemistry and preclinical aspects. Curr. Med. Chem. 19(23), 3982-3999 (2012
22. Ghate M, Jain SV. Structure based lead optimization approach in discovery of selective DPP4 inhibitors. Mini-Rev. Med. Chem. 13(6), 888-914 (2013
23. Juillerat-Jeanneret L. Dipeptidyl peptidase IV and its inhibitors: Therapeutics for type 2 diabetes and what else?. J. Med. Chem. 57(6), 2197-2212 (2014
24. Lambeir AM, Durinx C, Scharpe S et al. Dipeptidylpeptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit. Rev. Clin. Lab. Sci. 40(3), 209-294 (2003
25. Rasmussen HB, Branner S, Wiberg FC et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 10(1), 19-25 (2003
26. Reinhold D, Kähne T, Steinbrecher A et al. The role of dipeptidyl peptidase IV (DP IV) enzymatic activity in T cell activation and autoimmunity. Biol. Chem. 383(7-8), 1133-1138 (2002
27. Yu DMT, Yao TW, Chowdhury S et al. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J. 277(5), 1126-1144 (2010
28. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214(3), 829-835 (1993
29. Marguet D, Baggio L, Kobayashi T et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc. Natl Acad. Sci. USA 97(12), 6874-6879 (2000
30. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr. Rev. 20(6), 876-913 (1999
31. Kuhn B, Hennig M, Mattei P. Molecular recognition of ligands in dipeptidyl peptidase IV. Curr. Top. Med. Chem. 7(6), 609-619 (2007
32. Zettl H, Schubert-Zsilavecz M, Steinhilber D. Medicinal chemistry of incretin mimetics and DPP-4 inhibitors. ChemMedChem 5(2), 179-185 (2010
33. Chen T, Ajami K, McCaughan GW et al. Dipeptidyl peptidase IV gene family. The DPIV family. Adv. Exp. Med. Biol. 524, 79-86 (2003
34. Lankas GR, Leiting B, Roy RS et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: Potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 54(10), 2988-2994 (2005
35. Chiravuri M, Schmitz T, Yardley K et al. A novel apoptotic pathway in quiescent lymphocytes identified by inhibition of a post-proline cleaving aminodipeptidase: A candidate target protease, quiescent cell proline dipeptidase. J. Immunol. 163(6), 3092-3099 (1999
36. Burkey BF, Hoffmann PK, Hassiepen U et al. Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes. Obes. Metab. 10(11), 1057-1061 (2008
37. ClinicalTrials.gov. http://clinicaltrials.gov
38. Villhauer EB, Brinkman JA, Naderi GB et al. 1-[2-[(5-cyanopyridin-2-yl) amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 45(12), 2362-2365 (2002
39. Villhauer EB, Brinkman JA, Naderi GB et al. 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. 46(13), 2774-2789 (2003
40. Brandt I, Joossens J, Chen X et al. Inhibition of dipeptidylpeptidase IV catalyzed peptide truncation by vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl) amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem. Pharmacol. 70(1), 134-143 (2005
41. Stamataros G, Schneider SH. Vildagliptin in the treatment of type 2 diabetes mellitus. Expert Opin. Pharmacother. 12(12), 1967-1973 (2011
42. Scheen AJ. A review of gliptins in 2011. Expert Opin. Pharmacother. 13(1), 81-99 (2012
43. Cho TP, Gang LZ, Long YF et al. Synthesis and biological evaluation of bicyclo[3.3.0]octane derivatives as dipeptidyl peptidase 4 inhibitors for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 20(12), 3521-3525 (2010
44. Thomas A: WO2006040625 (2006
45. Madar DJ, Kopecka H, Pireh D et al. Discovery of 2-[4-{{2-(2S,5R)-2- cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]-4-methyl-1-piperidinyl] -4-pyridinecarboxylic acid (ABT-279): A very potent, selective, effective, and well-Tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes. J. Med. Chem. 49(21), 6416-6420 (2006
46. Fukushima H, Hiratate A, Takahashi M et al. Synthesis and structure-Activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 16(7), 4093-4106 (2008
47. Kato N, Oka M, Murase T et al. Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2- methylpropyl]-2-methyl pyrazolo[1,5-A]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor. Bioorg. Med. Chem. 19(23), 7221-7227 (2011
48. Ashworth DM, Atrash B, Baker GR et al. 2-cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. 6(10), 1163-1166 (1996
49. Hulin B, Cabral S, Lopaze MG et al. New fluorinated pyrrolidine and azetidine amides as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 15(21), 4770-4773 (2005
50. Caldwell CG, Chen P, He J et al. Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 14(5), 1265-1268 (2004
51. Augustyns KJL, Lambeir AM, Borloo M et al. Pyrrolidides: Synthesis and structure-Activity relationship as inhibitors of dipeptidyl peptidase IV. Eur. J. Med. Chem. 32(4), 301-309 (1997
52. Magnin DR, Robl JA, Sulsky RB et al. Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: Interplay between the N-Terminal amino acid alkyl side chain and the cyclopropyl group of alphaaminoacyl-l-cis-4,5-methanoprolinenitrile-based inhibitors. J. Med. Chem. 47(10), 2587-2598 (2004
53. Augeri DJ, Robl JA, Betebenner DA et al. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-Acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 48(15), 5025-5037 (2005
54. Thareja S, Aggarwal S, Malla P et al. Saxagliptin: A new drug for the treatment of type 2 diabetes. Mini-Rev. Med. Chem. 10(8), 759-765 (2010
55. Zhao G, Kwon C, Wang A et al. Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 23(6), 1622-1625 (2013
56. Sakashita H, Kitajima H, Nakamura M et al. 1-((S)-gammasubstituted prolyl)-(S)-2-cyanopyrrolidine as a novel series of highly potent DPP-IV inhibitors. Bioorg. Med. Chem. Lett. 15(10), 2441-2445 (2005
57. Kondo T, Nekado T, Sugimoto I et al. Design and synthesis of new potent dipeptidyl peptidase IV inhibitors with enhanced ex vivo duration. Bioorg. Med. Chem. 15(7), 2631-2650 (2007
58. Kondo T, Nekado T, Sugimoto I et al. Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group. Bioorg. Med. Chem. 16(4), 1613-1631 (2008
59. Ammirati MJ, Andrews KM, Boyer DD et al. (3,3-difluoropyrrolidin-1-yl)- [(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor. Bioorg. Med. Chem. Lett. 19(7), 1991-1995 (2009
60. Fukuda-Tsuru S, Anabuki J, Abe Y et al. A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur. J. Pharmacol. 696(1-3), 194-202 (2012
61. Yoshida T, Akahoshi F, Sakashita H et al. Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. 20(19), 5705-5719 (2012
62. Goda M, Kadowaki T. Teneligliptin for the treatment of Type 2 diabetes. Drug. Today. 49(10), 615-629 (2013
63. Xu J, Wei L, Mathvink R et al. Discovery of potent and selective phenylalanine based dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 15(10), 2533-2536 (2005
64. Liang GB, Qian X, Feng D et al. Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 17(7), 1903-1907 (2007
65. Biftu T, Feng D, Qian X et al. (3R)-4-[(3R)-3-Amino-4-(2,4,5- Trifluorophenyl)butanoyl]-3-(2,2,2-Trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 17(1), 49-52 (2007
66. Nitta A, Fujii H, Sakami S et al. (3R)-3-Amino-4-(2,4,5-Trifluorophenyl)- N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 18(20), 5435-5438 (2008
67. Nitta A, Fujii H, Sakami S et al. Novel series of 3-Amino-N-(4-Aryl-1,1- dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 22(23), 7036-7040 (2012
68. Pei Z, Li X, von Geldern TW et al. Discovery of ((4R,5S)-5-Amino-4-(2,4, 5-Trifluorophenyl)cyclohex-1-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-A]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 49(22), 6439-6442 (2006
69. Lam B, Zhang Z, Stafford JA et al. Structure-based design of pyridopyrimidinediones as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 22(21), 6628-6631 (2012
70. Jun MA, Park WS, Kang SK et al. Synthesis and biological evaluation of pyrazoline analogues with beta-Amino acyl group as dipeptidyl peptidase IV inhibitors. Eur. J. Med. Chem. 43(9), 1889-1902 (2008
71. Kim HJ, Kwak WY, Min JP et al. Dipeptidyl peptidase-4 inhibitor with beta-Amino amide scaffold: Synthesis, SAR and biological evaluation. Bioorg. Med. Chem. Lett. 22(17), 5545-5549 (2012
72. Ahn JH, Shin MS, Jun MA et al. Synthesis, biological evaluation and structural determination of beta-Aminoacylcontaining cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors. Bioorg. Med. Chem. Lett. 17(9), 2622-2628 (2007
73. Ahn JH, Park WS, Jun MA et al. Synthesis and biological evaluation of homopiperazine derivatives with beta-Aminoacyl group as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 18(24), 6525-6529 (2008
74. Cox JM, Harper B, Mastracchio A et al. Discovery of 3-Aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 17(16), 4579-4583 (2007
75. Edmondson SD, Mastracchio A, Cox JM et al. Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors. Bioorg. Med. Chem. Lett. 19(15), 4097-4101 (2009
76. Biftu T, Scapin G, Singh S et al. Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin. Bioorg. Med. Chem. Lett. 17(12), 3384-3387 (2007
77. Biftu T, Qian X, Chen P et al. Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3, 4-c]pyrazol-5(4H)-yl] tetrahydro-2H-pyran-3-Amine (23). Bioorg. Med. Chem. Lett. 23(19), 5361-5366 (2013
78. Brunavs M, Cowley P, Ward SW et al Recent disclosures of clinical candidates (SMR Award Lecture)-highlights from the society for medicines research symposium, held on December 5th 2012 at the national heart & lung institute (NHLI), London, UK. Drugs Fut. 38(2), 127-133 (2013
79. Peters JU, Hunziker D, Fischer H et al. An aminomethylpyrimidine DPP-IV inhibitor with improved properties. Bioorg. Med. Chem. Lett. 14(13), 3575-3578 (2004
80. Brigance RP, Meng W, Fura A et al. Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes. Bioorg. Med. Chem. Lett. 20(15), 4395-4398 (2010
81. Meng W, Brigance RP, Chao HJ et al. Discovery of 6-(aminomethyl)-5-(2,4- dichlorophenyl)-7-methylimidazo[1,2-A]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors. J. Med. Chem. 53(15), 5620-5628 (2010
82. Eckhardt M, Langkopf E, Mark M et al. 8-(3-(R)-Aminopiperidin-1-yl)-7- but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2, 6-dione (BI 1356), a highly potent, selective, long-Acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 50(26), 6450-6453 (2007
83. Rungby J. Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes. Expert Opin. Invest. Drugs 18(6), 835-838 (2009
84. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors similarities and differences. Drugs 71(11), 1441-1467 (2011
85. Huttner S, Graefe-Mody EU, Withopf B et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J. Clin. Pharmacol. 48(10), 1171-1178 (2008
86. Agrawal R, Jain P, Dikshit SN. Linagliptin: A novel methylxanthin based approved dipeptidyl peptidase-4 inhibitor. Curr. Drug. Targets. 13(7), 970-983 (2012
87. Nishio Y, Kimura H, Sawada N et al. 2-({6-[(3R)-3-Amino-3- methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3, 4-Tetrahydro-5H-pyrrolo[3, 2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): A potent, orally active dipeptidyl peptidase IV inhibitor without mechanismbased inactivation of CYP3A. Bioorg. Med. Chem. 19(18), 5490-5499 (2011
88. Brockunier LL, He J, Colwell LF et al. Substituted piperazines as novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 14(18), 4763-4766 (2004
89. 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. 7(6), 557-568 (2007
90. Kim D, Wang L, Beconi M et al. (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. 48(1), 141-151 (2005
91. Kim D, Kowalchick JE, Edmondson SD et al. Triazolopiperazine-Amides as dipeptidyl peptidase IV inhibitors: Close analogs of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 17(12), 3373-3377 (2007
92. Kim D, Kowalchick JE, Brockunier LL et al. Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-Aminoamides bearing subsituted triazolopiperazines. J. Med. Chem. 51(3), 589-602 (2008
93. Deacon CF. Dipeptidyl peptidase 4 inhibition with sitagliptin: A new therapy for type 2 diabetes. Expert Opin. Invest. Drugs 16(4), 533-545 (2007
94. Nordhoff S, Cerezo-Galvez S, Feurer A et al. The reversed binding of beta-phenethylamine inhibitors of DPP-IV: x-ray structures and properties of novel fragment and elaborated inhibitors. Bioorg. Med. Chem. Lett. 16(6), 1744-1748 (2006
95. Nordhoff S, Cerezo-Galvez S, Deppe H et al. Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. 19 (15), 4201-4203 (2009
96. Nordhoff S, Lopez-Canet M, Hoffmann-Enger B et al. From lead to preclinical candidate: Optimization of betahomophenylalanine based inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. 19(16), 4818-4823 (2009
97. Nordhoff S, Bulat S, Cerezo-Galvez S et al. The design of potent and selective inhibitors of DPP-4: Optimization of ADME properties by amide replacements. Bioorg. Med. Chem. Lett. 19(22), 6340-6345 (2009
98. Wright SW, Ammirati MJ, Andrews KM et al. (3R,4S)-4-(2,4,5- Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors of dipeptidyl peptidase IV: Synthesis, in vitro, in vivo, and x-ray crystallographic characterization. Bioorg. Med. Chem. Lett. 17(20), 5638-5642 (2007
99. Andrews KM, Beebe DA, Benbow JW et al. 1-((3S,4S)-4-Amino-1-(4- substituted-1,3,5-Triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 21(6), 1810-1814 (2011
100. Feng J, Zhang Z, Wallace MB et al. Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 50(10), 2297-2300 (2007
101. Deng J, Peng L, Zhang G et al. The highly potent and selective dipeptidyl peptidase IV inhibitors bearing a thienopyrimidine scaffold effectively treat type 2 diabetes. Eur. J. Med. Chem. 46(1), 71-76 (2011
102. Xie H, Zeng L, Zeng S et al. Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization. Eur. J. Med. Chem. 52, 205-212 (2012
103. Zhang Z, Wallace MB, Feng J et al. Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV. J. Med. Chem. 54(2), 510-524 (2011
104. Parsa KV, Pal M. Preclinical development of dipeptidyl peptidase IV inhibitor alogliptin: A brief overview. Expert Opin. Drug Discov. 6(8), 855-869 (2011
105. Deacon CF. Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Curr. Opin. Invest. Drugs 9(4), 402-413 (2008
106. Agrawal R, Bahare RS, Jain P et al. Novel serine protease dipeptidyl peptidase IV inhibitor: Alogliptin. Mini-Rev. Med Chem. 12(13), 1345-1358 (2012
107. Capuano A, Sportiello L, Maiorino MI et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy-focus on alogliptin. Drug Des. Devel. Ther. 7, 989-1001 (2013
108. DeFronzo RA, Fleck PR, Wilson CA et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: A randomized, double-blind, placebo-controlled study. Diabetes Care 31(12), 2315-2317 (2008
109. Cahn A, Raz I. Emerging gliptins for type 2 diabetes. Expert Opin. Emerg. Drugs 18(2), 245-258 (2013.