Discovery and structure - Activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors

Journal of Medicinal Chemistry

Volumn 50, Issue 8, 2007, Pages 1983-1987

  Pei, Zhonghua ^a   Li, Xiaofeng ^a   Von Geldern, Thomas W ^a   Longenecker, Kenton ^a   Pireh, Daisy ^a   Stewart, Kent D ^a   Backes, Bradley J ^a   Lai, Chunqiu ^a   Lubben, Thomas H ^a   Ballaron, Stephen J ^a   Beno, David W A ^a   Kempf Grote, Anita J ^a   Sham, Hing L ^a   Trevillyan, James M ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [6 [3 (METHYLSULFONYL)PHENYL]PYRIMIDIN 4 YL] 4 (2,4,5 TRIFLUOROPHENYL)PIPERIDIN 3 AMINE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GASTRIC INHIBITORY POLYPEPTIDE; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INCRETIN; PHENETHYLAMINE DERIVATIVE; PIPERIDINE DERIVATIVE; PIPERIDONE DERIVATIVE; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; ARTICLE; CRYSTAL STRUCTURE; DISTRIBUTION VOLUME; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; GLUCOSE HOMEOSTASIS; HIGH THROUGHPUT SCREENING; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ADENOSINE DEAMINASE; ANIMALS; ANTIGENS, CD26; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; GLYCOPROTEINS; HUMANS; MOLECULAR CONFORMATION; PHENETHYLAMINES; PIPERIDINES; PIPERIDONES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34247204289     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm061436d     Document Type: Article

References (37)

1. See: www.diabetes.org.
2. 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.; Thomberry, 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.
3. Miller, S. A.; St. Onge, E. L. Sitagliptin: A dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. Ann. Pharmcother. 2006, 40, 1336.
4. 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.
5. 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.
6. st Meeting of the American Chemical Society, Atlanta, GA, 2006; American Chemical Society: Washington, DC, 2006; MEDI-018.
7. Madar, D. J.; Kopecka, H.; Pireh, D.; Yong, H.; Pei, Z.; Li, X.; Wiedeman, P.; Djuric, S. W.; von Geldern, T. W.; Fickes, M.; Bhagavatula, L.; McDermott, T.; Wittenberger, S.; Richards, S. J.; Longenecker, K.; Stewart, K.; Lubben, T. H.; Ballaron, S. J.; Stashko, M. A.; Long, M.; Wells, H.; Zinker, B. A.; Mika, A. K.; Beno, D. W. A. Kempf-Grote, A. J.; Polakowski, J.; Segreti, J.; Reinhart, G. A.; Fryer, R.; Sham, H. L.; Trevilliyan, J. M. 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. 2006, 49, 6416-6420.
8. For reviews on DPP4 inhibitors, see (a) Green, B. D.; Flatt, P. R.; Bailey, C. J. Inhibition of dipeptidyl peptidase IV activity as a therapy of type 2 diabetes. Expert Opin. Emerging Drugs 2006, 11, 525-539.
9. (b) Gwaltney, S. L., II; Stafford, J. A. Inhibitors of dipeptidyl peptidase 4. Annu. Rep. Med. Chem. 2005, 40, 149-165.
10. (c) Weber, A. E. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 2004, 47, 4135-4141.
11. (d) Villhauer, E. B.; Coppola, G. M; Hughes, T. E. DPPIV inhibition and therapeutic potential. Annu. Rep. Med. Chem. 2001, 36, 191-200.
12. (a) Mojsov, S.; Weir. G. C; Habener, J. F. Insulinotropin: Glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. 1987, 79, 616-619.
13. (b) Kreymann, B.; Ghatei, M. A.; Williams, G.; Bloom, S. R. Glucagon-like peptide-1 7-36: A physiological incretin in man. Lancet 1987, 2, 1300-1304.
14. (c) Orskov, C.; Holst, J. J.; Nielsen, O. V. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 1988, 123, 2009-2013.
15. Nauck, M. A.; Heimesaat, M. M.; Behle, K.; Holst, J. J.; Nauck, M. S.; Ritzel, R.; Hufner, M.; Schmiegel, W. H. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J. Clin. Endocrinol. Metab. 2002, 87, 1239-1246.
16. (a) Wettergren, A.; Schjoldager, B.; Mortensen, P. E.; Myhre, J.; Christiansen, J.; Holst, J. J. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig. Dis. Sci. 1993, 38, 665-673.
17. (b) Nauck, M. A.; Niedereichholz, U.; Ettler, R.; Holst, J. J.; Orskov, C.; Ritzel, R.; Schmiegel, W. H. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulino-tropic effects in healthy humans. Am. J. Physiol. 1997, 273, E981-E988.
18. Holst, J. J. On the physiology of GIP and GLP-1. Horm. Metab. Res. 2004, 36, 747-754.
19. Meier, J. J. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract. Res., Clin. Endocrinol. Metab. 2004, 18, 587-606.
20. (a) Mentlein, R.; Ballwitz, B.; Schmidt, W. E. Dipeptidylpeptidase IV hydrolyses gastric inhibitory polypeptide, glucagonlike peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 1993, 214, 829-835.
21. (b) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, T. A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995, 136, 3585-3596.
22. (c) For a review, see: Deacon, C. F. Circulation and degradation of GIP and GLP-1. Horm. Metab. Res. 2004, 36, 761-765.
23. Pei, Z.; Li, X.; von Geldern, T. W.; Madar, D. J.; Longenecker, K.; Yong, H.; Lubben, T. H.; Stewart, K. D.; Zinker, B. A.; Backes, B. J.; Judd, A. S.; Mulhern, M.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D. W. A.; Reinhart, G. A.; Fryer, R. M.; Preusser, L. C.; Kempf-Grote, A. J.; Sham, H. L.; Trevillyan, J. M. 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. 2006, 49, 6439-6442.
24. Backes, B. J.; Longenecker, K.; Hamilton, G. L.; Stewart, K.; Lai, C.; Kopecka, H.; von Geldern, T. W.; Madar, D. J.; Pei, Z.; Lubben, T. H.; Zinker, B. A.; Tian, Z.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D. W. A.; Kempf-Grote, A. J.; Black-Schaefer, C.; Sham, H. L.; Trevillyan, J. M. Pyrrolidine-constrained phenethylamines: The design of potent, selective and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit. Bioorg. Med. Chem. Lett. 2007, doi: 10.1016/j.bmcl.2007.01.026.
25. Ono, N.; Kamimura, A.; Kaji, A. Michael addition of secondary nitroalkanes to β-substituted α,β-unsaturated compounds. Synthesis 1984, 226-227.
26. Klapars, A.; Huang, X.; Buchwald, S. L. A general and efficient copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc. 2002, 124, 7421-7428.
27. The details of this new methodology will be published elsewhere.
28. (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E. Catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. J. Am. Chem. Soc. 1999, 121, 10215-10216.
29. (b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. Development of a catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes for the synthesis of endothelin-A antagonist ABT-546. Scope, mechanism, and further application to the synthesis of the antidepressant Rolipram. J. Am. Chem. Soc. 2002, 124, 13097-13105.
30. For details, see Supporting Information.
31. (a) Corey, E. J.; Guzman-Perez, A.; Loh, T. P. Demonstration of the synthetic power of oxazaborolidine-catalyzed enantioselective Diels-Alder reactions by very efficient routes to cassiol and gibberellic acid. J. Am. Chem. Soc. 1994, 116, 3611-3612.
32. (b) For a review, see: Krapcho, A. P. Synthetic applications of dealkoxycarbonylations of malonate esters, β-keto esters, α-cyano esters and related compounds in dipolar aprotic media - Part I. Synthesis 1982, 805-914.
33. For details of the assay, see: Pei, Z.; Li, X.; Longenecker, K.; von Geldern, T. W.; Wiedeman, P. E.; Lubben, T. H.; Zinker, B. A.; Stewart, K.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D. W. A.; Long, M.; Wells, H.; Kempf-Grote, A. J.; Madar, D. J.; McDermott, T. S.; Bhagavatula, L.; Fickes, M. G.; Pireh, D.; Solomon, L. R.; Lake, M. R.; Edalji, R.; Fry, E. H.; Sham, H. L.; Trevillyan, J. M. Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2- cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors. J. Med. Chem. 2006, 49, 3520-3535.
34. (a) Cox, J. M.; Edmondson, S. D.; Harper, B.; Weber, A. E. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes. PCT Int. Appl. WO 2006039325, 2006.
35. (b) Edmondson, S. D.; Mastracchio, A.; Cox, J. M. Fused aminopiperidinobenzimidazoles as dipeptidyl peptidase-IV inhibitors, their preparation, pharmaceutical compositions, and use for the treatment or prevention of diabetes. PCT Int. Appl. WO 2006058064, 2006.
36. 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, Z.; 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.
37. Refined crystallographic coordinates for the structures of DPP4 complexed with 31 and 42 have been deposited in Protein Data Bank (www.rcsb.org) with entry codes 2OQI and 2OQV, respectively.