Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): Is DPP8-selectivity an attainable goal?

Journal of Medicinal Chemistry

Volumn 54, Issue 16, 2011, Pages 5737-5746

  Van Goethem, Sebastiaan ^a   Matheeussen, Veerle ^a   Joossens, Jurgen ^a   Lambeir, Anne Marie ^a   Chen, Xin ^b   De Meester, Ingrid ^a   Haemers, Achiel ^a   Augustyns, Koen ^a   Van Der Veken, Pieter ^a  

^a UNIVERSITY OF ANTWERP   (Belgium)

^b NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 4 [4 [(3 FLUOROPHENYL)(4 FLUOROPHENYL)METHYL] 3 METHYLPIPERAZIN 1 YL] 1 (ISOINDOLIN 2 YL)BUTANE 1,4 DIONE BIS(2,2,2 TRIFLUOROACETATE); 2 AMINO 4 [4 [(4 CHLOROPHENYL)(PHENYL)METHYL]PIPERAZIN 1 YL] 1 (5 FLUOROISOINDOLIN 2 YL)BUTANE 1,4 DIONE BIS(2,2,2 TRIFLUOROACETATE); 2 AMINO 4 [4 [(4 CHLOROPHENYL)(PHENYL)METHYL]PIPERAZIN 1 YL] 1 (ISOINDOLIN 2 YL)BUTANE 1,4 DIONE BIS(2,2,2 TRIFLUOROACETATE); 2 AMINO 4 [4 [BIS(4 FLUOROPHENYL)METHYL] 3 METHYLPIPERAZIN 1 YL] 1 (ISOINDOLIN 2 YL)BUTANE 1,4 DIONE BIS(2,2,2 TRIFLUOROACETATE); DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIPEPTIDYL PEPTIDASE; DIPEPTIDYL PEPTIDASE 8; DIPEPTIDYL PEPTIDASE 9; DIPEPTIDYL PEPTIDASE IV; ISOINDOLE DERIVATIVE; PIPERAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL MODIFICATION; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; STRUCTURE ACTIVITY RELATION;

AMINO ACID SEQUENCE; DIPEPTIDASES; DIPEPTIDYL-PEPTIDASES AND TRIPEPTIDYL-PEPTIDASES; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; HUMANS; ISOINDOLES; KINETICS; MODELS, CHEMICAL; MOLECULAR STRUCTURE; SEQUENCE HOMOLOGY, AMINO ACID; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80051862999     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200383j     Document Type: Article

References (48)

1. Augustyns, K.; Bal, G.; Thonus, G.; Belyaev, A.; Zhang, X. M.; Bollaert, W.; Lambeir, A. M.; Durinx, C.; Goossens, F.; Haemers, A. The unique properties of dipeptidyl-peptidase IV (DPP IV/CD26) and the therapeutic potential of DPP IV inhibitors Curr. Med. Chem. 1999, 6, 311-327 (Pubitemid 29226115)
2. Yu, D. M.; Yao, T. W.; Chowdhury, S.; Nadvi, N. A.; Osborne, B.; Church, W. B.; McCaughan, G. W.; Gorrell, M. D. The dipeptidyl peptidase IV family in cancer and cell biology FEBS J. 2010, 277, 1126-1144
3. Augustyns, K.; Van der Veken, P.; Senten, K.; Haemers, A. The therapeutic potential of inhibitors of dipeptidyl peptidase IV (DPP IV) and related proline-specific dipeptidyl aminopeptidases Curr. Med. Chem. 2005, 12, 971-998 (Pubitemid 40443851)
4. Van der Veken, P.; Haemers, A.; Augustyns, K. Prolyl peptidases related to dipeptidyl peptidase IV: potential of specific inhibitors in drug discovery Curr. Top. Med. Chem. 2007, 7, 621-635 (Pubitemid 46488284)
5. Busek, P.; Malik, R.; Sedo, A. Dipeptidyl peptidase IV activity and/or structure homologues (DASH) and their substrates in cancer Int. J. Biochem. Cell Biol. 2004, 36, 408-421 (Pubitemid 37542440)
6. Sedo, A.; Malik, R. Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities? Biochim. Biophys. Acta 2001, 1550, 107-116 (Pubitemid 34037997)
7. Rosenblum, J. S.; Kozarich, J. W. Prolyl peptidases: a serine protease subfamily with high potential for drug discovery Curr. Opin. Chem. Biol. 2003, 7, 496-504 (Pubitemid 36980841)
8. Demuth, H. U.; McIntosh, C. H.; Pederson, R. A. Type 2 diabetesr - therapy with dipeptidyl peptidase IV inhibitors Biochim. Biophys. Acta 2005, 1751, 33-44 (Pubitemid 41033292)
9. McIntosh, C. H.; Demuth, H. U.; Pospisilik, J. A.; Pederson, R. Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents? Regul. Pept. 2005, 128, 159-165 (Pubitemid 40380916)
10. 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. (2 R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H)-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 (Pubitemid 40105255)
11. 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 (Pubitemid 36702545)
12. 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. P.; 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, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes J. Med. Chem. 2005, 48, 5025-5037 (Pubitemid 41033142)
13. Gerich, J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res. Clin. Pract. 2010, 90, 131-140
14. Mulakayala, N.; Reddy, C. H. U.; Iqbal, J.; Pal, M. Synthesis of dipeptidyl peptidase-4 inhibitors: a brief overview Tetrahedron 2010, 66, 4919-4938
15. van Genugten, R. E.; van Raalte, D. H.; Diamant, M. Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide Diabetes Res. Clin. Pract. 2009, 86 (Suppl 1) S26-S34
16. Ahren, B. DPP-4 inhibitors Best Pract. Res. Clin. Endocrinol. Metab. 2007, 21, 517-533 (Pubitemid 350185859)
17. Verspohl, E. J. Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors Pharmacol. Ther. 2009, 124, 113-138
18. Lambeir, A. M.; Scharpe, S.; De Meester, I. DPP4 inhibitors for diabetest - what next? Biochem. Pharmacol. 2008, 76, 1637-1643
19. Yazbeck, R.; Howarth, G. S.; Abbott, C. A. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol. Sci. 2009, 30, 600-607
20. Juillerat-Jeanneret, L.; Gerber-Lemaire, S. The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders Mini-Rev. Med. Chem. 2009, 9, 215-226
21. Tsai, T. Y.; Yeh, T. K.; Chen, X.; Hsu, T.; Jao, Y. C.; Huang, C. H.; Song, J. S.; Huang, Y. C.; Chien, C. H.; Chiu, J. H.; Yen, S. C.; Tang, H. K.; Chao, Y. S.; Jiaang, W. T. Substituted 4-Carboxymethylpyroglutamic Acid Diamides as Potent and Selective Inhibitors of Fibroblast Activation Protein J. Med. Chem. 2010, 53, 6572-6583
22. Maes, M. B.; Scharpe, S.; De Meester, I. Dipeptidyl peptidase II (DPPII), a review Clin. Chim. Acta 2007, 380, 31-49 (Pubitemid 46498040)
23. Senten, K.; Van der Veken, P.; Bal, G.; De Meester, I.; Lambeir, A. M.; Scharpe, S.; Bauvois, B.; Haemers, A.; Augustyns, K. Development of potent and selective dipeptidyl peptidase II inhibitors Bioorg. Med. Chem. Lett. 2002, 12, 2825-2828 (Pubitemid 35266742)
24. Senten, K.; Van der Veken, P.; De Meester, I.; Lambeir, A. M.; Scharpe, S.; Haemers, A.; Augustyns, K. Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases J. Med. Chem. 2003, 46, 5005-5014 (Pubitemid 37352037)
25. Senten, K.; Van Der Veken, P.; De Meester, I.; Lambeir, A. M.; Scharpe, S.; Haemers, A.; Augustyns, K. Gamma-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors J. Med. Chem. 2004, 47, 2906-2916 (Pubitemid 38656744)
26. Olsen, C.; Wagtmann, N. Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV Gene 2002, 299, 185-193 (Pubitemid 35379840)
27. Chen, T.; Ajami, K.; McCaughan, G. W.; Gorrell, M. D.; Abbott, C. A. Dipeptidyl peptidase IV gene family. The DPIV family Dipept. Aminopept.: Basic Sci. Clin. Appl. 2003, 524, 79-86 (Pubitemid 36570813)
28. Abbott, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.; McCaughan, G. W.; Gorrell, M. D. Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8 Eur. J. Pharmacol. 2000, 267, 6140-6150
29. Dubois, V.; Lambeir, A. M.; Van der Veken, P.; Augustyns, K.; Creemers, J.; Chen, X.; Scharpe, S.; De Meester, I. Purification and characterization of dipeptidyl peptidase IV-like enzymes from bovine testes Front. Biosci. 2008, 13, 3558-3568 (Pubitemid 351594704)
30. Dubois, V.; Lambeir, A. M.; Vandamme, S.; Matheeussen, V.; Guisez, Y.; Scharpe, S.; De Meester, I. Dipeptidyl peptidase 9 (DPP9) from bovine testes: identification and characterization as the short form by mass spectrometry Biochim. Biophys. Acta 2010, 1804, 781-788
31. Bjelke, J. R.; Kanstrup, A. B.; Rasmussen, H. B. Selectivity among dipeptidyl peptidases of the S9b family Cell. Mol. Biol. 2006, 52, 3-7 (Pubitemid 46683314)
32. Ajami, K.; Pitman, M. R.; Wilson, C. H.; Park, J.; Menz, R. I.; Starr, A. E.; Cox, J. H.; Abbott, C. A.; Overall, C. M.; Gorrell, M. D. Stromal cell-derived factors 1alpha and 1beta, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8 FEBS Lett. 2008, 582, 819-825
33. Rummey, C.; Metz, G. Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site Proteins 2007, 66, 160-171 (Pubitemid 44955988)
34. Yu, D. M.; Ajami, K.; Gall, M. G.; Park, J.; Lee, C. S.; Evans, K. A.; McLaughlin, E. A.; Pitman, M. R.; Abbott, C. A.; McCaughan, G. W.; Gorrell, M. D. The in vivo expression of dipeptidyl peptidases 8 and 9 J. Histochem. Cytochem. 2009, 57, 1025-1040
35. Matheeussen, V. B. L.; De Meyer, G.; De Keulenaer, G.; Van der Veken, P.; Augustyns, K.; Dubois, V.; Scharpé, S.; De Meester, I. Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries Biol. Chem. 2010, 392, 189-198
36. Maes, M. B.; Dubois, V.; Brandt, I.; Lambeir, A. M.; Van der Veken, P.; Augustyns, K.; Cheng, J. D.; Chen, X.; Scharpe, S.; De Meester, I. Dipeptidyl peptidase 8/9-like activity in human leukocytes J. Leukocyte Biol. 2007, 81, 1252-1257 (Pubitemid 46702044)
37. Geiss-Friedlander, R.; Parmentier, N.; Moller, U.; Urlaub, H.; Van den Eynde, B. J.; Melchior, F. The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides J. Biol. Chem. 2009, 284, 27211-27219
38. Zhu, H.; Zhou, Z. M.; Lu, L.; Xu, M.; Wang, H.; Li, J. M.; Sha, J. H. Expression of a novel dipeptidyl peptidase 8 (DPP8) transcript variant, DPP8-v3, in human testis Asian J. Androl. 2005, 7, 245-255 (Pubitemid 41288546)
39. Lankas, G. R.; Leiting, B.; Roy, R. S.; Eiermann, G. J.; Beconi, M. G.; Biftu, T.; Chan, C. C.; Edmondson, S.; Feeney, W. P.; He, H.; Ippolito, D. E.; Kim, D.; Lyons, K. A.; Ok, H. O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.; Qian, X.; Reigle, L.; Woods, A.; Wu, J. K.; Zaller, D.; Zhang, X.; Zhu, L.; Weber, A. E.; Thornberry, N. A. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9 Diabetes 2005, 54, 2988-2994 (Pubitemid 41401097)
40. Connolly, B. A.; Sanford, D. G.; Chiluwal, A. K.; Healey, S. E.; Peters, D. E.; Dimare, M. T.; Wu, W.; Liu, Y.; Maw, H.; Zhou, Y.; Li, Y.; Jin, Z.; Sudmeier, J. L.; Lai, J. H.; Bachovchin, W. W. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety J. Med. Chem. 2008, 51, 6005-6013
41. Burkey, B. F.; Hoffmann, P. K.; Hassiepen, U.; Trappe, J.; Juedes, M.; Foley, J. E. Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited Diabetes, Obes. Metab. 2008, 10, 1057-1061
42. Wu, J. J.; Tang, H. K.; Yeh, T. K.; Chen, C. M.; Shy, H. S.; Chu, Y. R.; Chien, C. H.; Tsai, T. Y.; Huang, Y. C.; Huang, Y. L.; Huang, C. H.; Tseng, H. Y.; Jiaang, W. T.; Chao, Y. S.; Chen, X. Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor Biochem. Pharmacol. 2009, 78, 203-210
43. Van Goethem, S.; Van der Veken, P.; Dubois, V.; Soroka, A.; Lambeir, A. M.; Chen, X.; Haemers, A.; Scharpe, S.; De Meester, I.; Augustyns, K. Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 2: isoindoline containing inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 4159-4162
44. Van der Veken, P.; De Meester, I.; Dubois, V.; Soroka, A.; Van Goethem, S.; Maes, M. B.; Brandt, I.; Lambeir, A. M.; Chen, X.; Haemers, A.; Scharpe, S.; Augustyns, K. Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 1: identification of dipeptide derived leads Bioorg. Med. Chem. Lett. 2008, 18, 4154-4158
45. Van der Veken, P.; Soroka, A.; Brandt, I.; Chen, Y. S.; Maes, M. B.; Lambeir, A. M.; Chen, X.; Haemers, A.; Scharpe, S.; Augustyns, K.; De Meester, I. Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates J. Med. Chem. 2007, 50, 5568-5570 (Pubitemid 350106012)
46. Jiaang, W. T.; Chen, Y. S.; Hsu, T.; Wu, S. H.; Chien, C. H.; Chang, C. N.; Chang, S. P.; Lee, S. J.; Chen, X. Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8 Bioorg. Med. Chem. Lett. 2005, 15, 687-691 (Pubitemid 40143148)
47. Lu, I. L.; Lee, S. J.; Tsu, H.; Wu, S. Y.; Kao, K. H.; Chien, C. H.; Chang, Y. Y.; Chen, Y. S.; Cheng, J. H.; Chang, C. N.; Chen, T. W.; Chang, S. P.; Chen, X.; Jiaang, W. T. Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors Bioorg. Med. Chem. Lett. 2005, 15, 3271-3275 (Pubitemid 40799072)
48. Villhauer, E. B. N -(Substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV. U.S. Patent US 6,166,063, December 26, 2000.