Unequivocal role of pyrazine ring in medicinally important compounds: A review

Mini-Reviews in Medicinal Chemistry

Volumn 13, Issue 11, 2013, Pages 1607-1625

  Miniyar, Pankaj B ^a   Murumkar, Prashant R ^a   Patil, Pallavi S ^a   Barmade, Mahesh A ^a   Bothara, Kailash G ^a  

^a Sinhgad Institute of Pharmacy   (India)

Author keywords

Anti diabetic agents; Anti tubercular agents; Anticancer agents; Diuretics; Pyrazine

Indexed keywords

1, 2 DICARBONYL DERIVATIVE; ACIPIMOX; AMILORIDE; AMINOKETONE; ANTINEMATODAL AGENT; AURORA KINASE INHIBITOR; B RAF KINASE INHIBITOR; BENZAMIL; BORTEZOMIB; CASPASE 3 INHIBITOR; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR3 ANTAGONIST; CORTICOTROPIN RELEASING FACTOR ANTAGONIST; EFAVIRENZ; ETHANOLAMINE; GLIPIZIDE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MORINAMIDE; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; OXYTOCIN ANTAGONIST; PROTEIN KINASE INHIBITOR; PYRAZINAMIDE; PYRAZINE; RHO KINASE INHIBITOR; SOMATOMEDIN C; TETRAMETHYLPYRAZINE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASOPRESSIN ANTAGONIST;

APOPTOSIS; BIOLOGICAL ACTIVITY; BREAST CANCER; CELL CYCLE PROGRESSION; CHROMOSOMAL INSTABILITY; DEGRADATION; DEHYDROGENATION; DRUG SYNTHESIS; GLAUCOMA; GRAFT REJECTION; HUMAN; HYPERTENSION; KIDNEY DISEASE; MINIMUM INHIBITORY CONCENTRATION; MULTIPLE SCLEROSIS; NEOPLASM; NONHUMAN; POLYMERIZATION; PSORIASIS; REVIEW; RHEUMATOID ARTHRITIS;

ANTINEOPLASTIC AGENTS; ANTITUBERCULAR AGENTS; DIABETES MELLITUS; DIURETICS; HUMANS; HYPOGLYCEMIC AGENTS; KIDNEY; MYCOBACTERIUM TUBERCULOSIS; NEOPLASMS; PROTEIN KINASE INHIBITORS; PYRAZINES;

EID: 84888070927     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/1389557511313110007     Document Type: Review

References (124)

1. Barlin, G. B. The Pyrazines: The Chemistry of Heterocyclic Compounds: A series of monographs, John Wiley & Sons, New York, 1982, 41, pp. 1-10.
2. Rappert, M. R. Pyrazines: Occurrence, Formation and Biodegradation. Appl. Microbiol. Biotechnol, 2010, 85, 1315-20.
3. th ed.; New age international (P) Ltd, 2005, pp. 528-32.
4. Joule, J. A.; Mill, K. Heterocyclic Chemistry, 4th ed.; Blackwell publishing, UK, 2002, pp. 221-22.
5. Kress, T. J.; Varie, D. L. six-membered ring systems: Diazines and benzo derivatives. Progress in heterocyclic chemistry, 1991, 3, 205-22.
6. Padwa, A.; Dharan, M.; Smolanoff, J.; wetmove, S. I. jr. Photochemical transformations of small ring heterocyclic compounds. XLVII. Electronic details of the photocycloaddition of arylazines. J. Am. Chem. Soc, 1973, 95, 1945-54.
7. Aston, J. G.; Peterson, T. E.; Holowchak, J. The synthesis of pyrazine by the catalytic dehydrogenation of ethanolamine. J. Am. Chem. Soc, 1994, 56, 153-54.
8. Formation of pyrazines from the mailard reaction of glucose & glutamine-amide-15N. J. Agri. Food. Chem, 1993, 41, 2112-15.
9. Barlin, G. B. The Pyrazines: The Chemistry of Heterocyclic Compounds: A series of monographs, John Wiley & Sons, New York, 1982, Vol. 41, pp. 87.
10. Mattey, M.; Harle, E. M. Aerobic metabolism of pyrazine compounds by a pseudomonas species. Biochem. Soc. Trans, 1976, 4, 492-94.
11. Adams, J.; Kauffman, M. Development of the Proteasome Inhibitor Velcade (Bortezomib). Cancer Invest, 2004, 22, 304-11.
12. Cohen, P. Protein kinases-the major drug targets of the twenty-first century? Rev. Drug Disc, 2002, 1, 309-15.
13. Matthews, T. P.; Klair, S.; McHardy, T.; Boxall, K.; Fisher, M.; Cherry, M.; Allen, C. E.; Addison, G. J.; Ellard, J.; Aherne, G. W.; Westwood, I. M.; Montfort, R. V.; Garrett, M. D.; Reader, J. C.; Collins, I. Design and evaluation of 3, 6-di(hetero)aryl imidazo[1, 2-a]pyrazines as inhibitors of checkpoint and other kinases. Bioorg. Med. Chem. Lett, 2010, 20, 4045-49.
14. Dubinina, G. G.; Platonov, M. O.; Golovach, S. M.; Borysko, P. O.; Tolmachov, A. O.; Volovenko, Y. M. Novel 5, 7-disubstituted 6-amino-5H-pyrrolo [3, 2-b]pyrazine-2, 3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity. Eur. J. Med. Chem, 2006, 41, 727-37.
15. Kimura, M.; Matsuda, Y.; Yoshioka, T. Cell cycle dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J. Biol. Chem, 1999, 274, 7334-40.
16. Tanaka, T.; Kimura, M.; Matsunaga, K.; Fukada, D.; Mori, H.; Okano, Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res, 1999, 59, 2041-44.
17. Reiter, R.; Gais, P.; Jeutting, U.; Steuer-Vogt, M. K.; Pickhard, A.; Bink, K.; Rauser, S.; Lassmann, S.; Hofler, H.; Werner, M.; Walch, A. Aurora kinase-A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin. Cancer Res, 2006, 12, 5136-41.
18. Gritsko, T. M.; Coppola, D.; Paciga, J. E.; Yang, L.; Sun, M.; Shelley, S. A.; Fiorica, J. V.; Nicosia, S. V.; Cheng, J. Q. Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin. Cancer Res, 2003, 9, 1420-26.
19. Lee, E. C.; Frolov, A.; Li, R.; Ayala, G.; Greenberg, N. M. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res, 2006, 66, 4996-02.
20. Kerekes, A. D.; Esposite, S. R.; Doll, R. J.; Tagat, J. R.; Yu, T.; Xiao, Y.; Zhang, Y.; Prelusky, D. B.; Tevar, S.; Gray, K.; Terracina, G. A.; Lee, S.; Jones, J.; Liu, M.; Basso, A. D.; Smith, E. B. Aurora kinase inhibitors based on the imidazo[1, 2-a]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure. J. Med. Chem, 2011, 54, 201-10.
21. Murnion, M. E.; Adams, R. R.; Callister, D. M.; Allis, C. D.; Earnshaw, W. C.; Swedlow, J. R. Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation. J. Biol. Chem, 2001, 276, 26656-65.
22. Belanger, D. B.; Curran, P. J.; Hruza A.; Voigt, J.; Meng, Z.; Mandal, A. K.; Siddiqui, M. A.; Basso, A. D.; Gray, K. Discovery of imidazo[1, 2-a]pyrazine-based Aurora kinase inhibitors. Bioorg. Med. Chem. Lett, 2010, 20, 5170-74.
23. Yu, T.; Tagat, J. R.; Kerekes, A. D.; Doll, R. J.; Zhang, Y.; Xiao, Y.; Esposite, S.; Belanger, D. B.; Curran, P. J.; Mandal, A. K.; Siddqui, M. A.; Shih, N.; Basso, A. D.; liu, M.; gray, K.; Tevar, S.; Jones, J.; Lee, S.; Liang, L.; Ponery, S.; Smith, E. B.; Hruza, A.; Voigt, J.; Ramanathan, L.; Prosise, W.; Hu, M. Discovery of a potent, injectable inhibitor of aurora kinases based on the imidazo-[1, 2-]-pyrazine core. ACS Med. Chem. Lett, 2010, 1, 214-18.
24. Hayward, D. G.; Fry, A. M. Nek2 kinase in chromosome instability and cancer. Cancer Lett, 2006, 237, 155-66.
25. Whelligan, D. K.; Solanki, S.; Taylor, D.; Thomson, D. W.; Cheung, K. M. J.; Boxall, K.; Mas-Droux, C.; Barillari, C.; Burns, S.; Grummitt, C. G.; Collins, I.; Aherne, G. W.; Bayliss, R.; Hoelder, S. Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization. J. Med. Chem, 2010, 53, 7682-98.
26. Chiloeches, A.; Marais, R. Mitogen-activated protein kinase cascades as therapeutic targets in cancer. Targets for cancer chemotherapy: transcription factors and other nuclear proteins; Humana Press Inc.: Totowa, 2002; 179-06.
27. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I. J.; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J. Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold: generation of a nanomolar lead. J. Med. Chem, 2006, 49, 407-16.
28. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I. J; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J.; Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2, 6-disubstituted pyrazine scaffold. J. Med. Chem, 2008, 51, 3261-74.
29. Kastan, M. B.; Onyekwere, O.; Sidransky, D.; Vogelstein, B.; Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res, 1991, 51, 6304-11.
30. Zhao, H.; Watkins, J. L.; Piwnica-Worms, H. Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14795-00.
31. Li, G.; Hasvold, L. A.; Tao, Z. F.; Wang, G. T.; Gwaltney, S. L.; Patel, J.; Kovar, P.; Credo, R. B.; Chen, Z.; Zhang, H.; Park, C.; Sham, H. L.; Sowin, T.; Rosenberg, S. H.; Lin, N.; Synthesis and biological evaluation of 1-(2, 4, 5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors. Bioorg. Med. Chem. Lett, 2006, 16, 2293-98.
32. Wang, G. T.; Li, G.; Mantei, R. A.; Chen, Z.; Kovar, P.; Gu, W.; Xiao, Z.; Zhang, H.; Sham, H. L.; Sowin, T.; Rosenberg, S. H.; Lin, N. 1-(5-Chloro-2-alkoxyphenyl)-3-(5-cyanopyrazi-2-yl)ureas as potent and selective inhibitors of Chk1 kinase: synthesis, preliminary SAR and biological activities. J. Med. Chem, 2005, 48, 3118-21.
33. Lainchbury, M.; Matthews, T.; Mchardy, T.; Boxall, K. J.; Walton, M. I.; Eve, P. D.; hayes, A.; Valenti, M. R.; Brandon, A. K.; Box, G.; Aherne, G. W.; Reader, J. C.; Raynaud, F. I.; Eccles, S. A.; Garrett, M. D.; Collins, I. Discovery of 3-alkoxyamino-5-(pyridine-2-ylamino)pyrazine-2-carbonotriles as selective, orally bioavailable CHK1 inhibitors. J. Med. Chem, 2012, 55, 10229-40.
34. Myadaraboina, S.; Alla, M.; Saddanapu, V.; Bommenaa, V.; Addlagatta, A. Structure activity relationship studies of imidazo[1, 2-a]pyrazine derivatives against cancer cell lines. Eur. J. Med. Chem, 2010, 45, 5208-16.
35. Pan, X.-H.; Liu, X.; Zhao, B.-X.; Xie, Y.-S.; Shin, D.-S.; Zhang, S.-L.; Zhao, J.; Miao, J.-Y.; 5-Alkyl-2-ferrocenyl-6, 7-dihydropyrazolo[1, 5-a]pyrazin-4(5H)-one derivatives inhibit growth of lung cancer A549 cell by inducing apoptosis. Bioorg. Med Chem, 2008, 16(20), 9093-00.
36. Zhang, J. H.; Fan, C. D.; Zhao, B. X.; Shin, D. S.; Xie, W.; Miao, J. Y.; Synthesis and preliminary biological evaluation of novel pyrazolo[1, 5-a]pyrazin-4(5H)-one derivatives as potential agents against A549 lung cancer cells. Bioorg. Med. Chem, 2008, 16, 10165-71.
37. Zhang, G.; Liu, Y.; Wang, S.; Zhou, C.; Huang, Q.; Gong, P. Synthesis and cytotixicity studies of novel 2-Hydrazonylpyrido [2, 3-b]pyrazine-3(4H)-ones. Arch. Pharm. Chem. Life Sci, 2012, 345, 49-56.
38. Crew, A. P.; Bhagwat, S. V.; Dong, H.; Bittner, M. A.; Chan, A.; Chen, X.; Coate, H.; Cooke, A.; Gokhale, P. C.; Honda, A.; Jin, M.; Kahler, J.; Mantis, C.; Mulvihill, M. J.; Tavares-Greco, P. A.; Volk, B.; Wanga, J.; Werner, D. S.; Arnold, L. D.; Pachter, J. A.; Wild, R.; Gibson, N. W. Imidazo[1, 5-a]pyrazines: Orally efficacious inhibitors of mTORC1 and mTORC2. Bioorg. Med. Chem. Lett, 2011, 21, 2092-97.
39. Mortensen, D. S.; Perrin-Ninkovic, S. M.; Harris, R.; Lee, B. G. S.; Shevlin, G.; Hickman, M.; Khambatta, G.; Bisonette, R. R.; Fultz, K. E.; Sankar, S. Discovery and SAR exploration of a novel series of imidazo[4, 5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors. Bioorg. Med. Chem. Lett, 2011, 21, 6793-99.
40. Han, Y.; Giroux, A.; Colucci, J.; Bayly, C. I.; Mckay, D. J.; Roy, S.; Xanthoudakis, S.; Vaillancourt, J.; Rasper, D. M.; Tam, J.; Tawa, P.; Nicholsonb, D. W.; Zamboni, R. J.; Novel pyrazinone monoamides as potent and reversible caspase-3 inhibitors. Bioorg. Med. Chem. Lett, 2005, 15, 1173-80.
41. De, M. P.; Whittaker, J. Structural biology of insulin and IGF-1 receptors: implications for drug design. Nat. Rev. Drug. Disc, 2002, 1, 769-83.
42. Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer, 2008, 8, 915-28.
43. Jin, M.; Kleinberg, A.; cooke, A.; Gokhale, P. C.; Foreman, K.; Dong, H.; Siu, K. W.; Bittner, M. A.; Mulvihill, K. M.; Yao, Y.; Landfair, D.; O'conner, M.; Mak, G.; Pachter, J. A.; Wild, R.; Franklin, M. S.; Ji, Q.; Mulvihill, M. J. Potent and selective cyclohexyl derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy. Bioorg. Med. Chem. Lett, 2011, 21, 1176-80.
44. Manser, E.; Leung, T.; Salihuddin, H.; Tan, L.; Lim, L. A nonreceptor tyrosine kinase that inhibits the GTPase activity of P21cdc42. Nature, 1993, 27, 364-67.
45. Prieto-Echague, V.; Miller, W. T. J. Regulation of ACK-Family nonreceptor tyrosine kinase., Signal Transduct, 2011, 9 pages, article ID 742372.
46. Van der Horst, E. H.; Degenhardt, Y. Y.; Strelow, A.; Slavin, A.; Chinn, L.; Orf, J.; Rong, M.; Li, S.; See, L. H.; Nguyen, K. Q.; Hoey, T.; Wesche, H.; Powers, S. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1., Proc Natl. Acad. Sci, 2005, 102, 15901-06.
47. Mahajan, K.; Coppola, D.; Challa, S.; Fang, B.; Chen, Y. A.; Zhu, W.; Lopez, A. S.; Koomen, J.; Engelman, R. W.; Rivera, C.; Muraoka-Cook, R. S.; Cheng, J. Q.; Schönbrunn, E.; Sebti, S. M.; Earp, H. S.; Mahajan, N. P. ACK1 mediated AKT/PKB tyrosine 176 phosphorylation regulates it's activation. PLoS One, 2010, 5, e9646.
48. Jin, M.; wang, J.; Kleinberg, A.; Kadalbajoo, M.; siu, K. W.; Cooke, A.; Bittner, M. A.; Yao, Y.; Thelamann, A.; ji, Q.; Bhagwat, S.; Mulvihill, K. S.; Rechka, J. A.; Pachter, J. A.; Crew, A. P.; Epstin, D.; Mulvihill, M. J. Discovery of potent, selective and orally bioavailable imidazo[1, 5-]pyrazine derived ACK1 inhibitors. Bioorg. Med. Chem. Lett, 2013, 23, 979-84.
49. Kotlyarov, A.; Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk, H. MAPKAP kinase 2 is essential for LPS-induced TNFalpha biosynthesis. Nat. Cell Biol, 1999, 1, 94-97.
50. Neininger, A.; Kontoyiannis, D.; Kotlyarov, A.; Winzen, R.; Eckert, R.; Volk, H. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J. Biol. Chem, 2002, 277, 3065-68.
51. Lin, S.; Lombardo, M.; Malkani, S.; Hale, J. J.; Mills, S. G.; Chapman, K.; Thompson, J. E.; Zhang, W. X.; Wang, R.; Cubbon, R. M.; O'Neill, E. A.; Luell, S.; Carballo-Jane, E.; Yang, L. Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas as potent inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem. Lett, 2009, 19, 3238-42.
52. Du, X.; Gustin, D. J.; Chen, X.; Duquette, J.; McGee, L. R.; Wang, Z.; Ebsworth, K.; Henne, K.; Lemon, B.; Ma, J.; Miao, S.; Sabalan, E.; Sullivan, T. J.; Tonn, G.; Collins, T. L.; Medina, J. C. Imidazopyrazine derivatives as potent CXCR3 antagonists. Bioorg. Med. Chem. Lett, 2009, 19, 5200-04.
53. Medina, J.; Johnson, M. G.; Collins, T. L. CXCR3 Antagonists. Ann. Rep. Med. Chem. 2005, 40, 215-25.
54. Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2, 3-Diaminopyrazines as rho kinase inhibitors. Bioorg. Med. Chem. Lett, 2010, 20, 1137-40.
55. Breitenlechner, C.; Gabel, M.; Engh, R.; Bossemeyer, D. Structural insights into AGC kinase inhibition Oncol. Res, 2004, 14, 267-78.
56. Amino, M.; Fukara, Y.; Kaibuchi, K. Regulation and functions of rho-associated kinase. Exp. Cell Biol, 2000, 261, 44-51.
57. Riento K.; Ridley A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol, 2003, 4, 446-56.
58. Somlyo, A. P.; Somlyo, A. V. Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and nonmuscle myosin II. J. Physiol, 2000, 522, 177-85.
59. st ed.; Back bay books; 1994, pp 3-31.
60. Sriram, D.; Yogeeswari, P.; and Reddy, S. P. Synthesis of pyrazinamide mannich bases and its antitubercular properties. Bioorg. Med. Chem. Lett, 2006, 16, 2113-6.
61. Vergara, F. M. F.; Camilo H. da S. Lima; Maria das Graças M. de O. Henriques; Cande A. P. L.; Lourenço, M. C. S.; Ferreira, M. L.; Kaiser, C. R.; Souza, M. V. N. Synthesis and antimycobacterial activity of N'-(E)-(monosubstitutedbenzylidene)]-2-pyrazinecarbohydrazide derivatives. Eur. J. Med. Chem, 2009, 44, 4954-59.
62. Seitz, L. E.; Suling, W. J.; Reynolds, R. C. Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. J. Med. Chem, 2002, 45, 5604-06.
63. Dolezal, M.; Cmedlova, P.; Palek, L.; Vinsova, J.; Kunes, J.; Buchta, V.; Jampilek, J.; Kralova, K. Synthesis and antimycobacterial evaluation of substituted pyrazinecarboxamides. Eur. J. Med. Chem, 2008, 43, 1105-13.
64. Zitko, J.; Dolezal, M.; Svobodova, M.; Vejsova, M.; Kunes, J.; Kucera, R.; Jilek, P. Synthesis and antimycobacterial properties of N-substituted 6-amino-5-cyanopyrazine-2-carboxamides. Bioorg. Med. Chem, 2011, 19, 1471-76.
65. Mathew, B.; Srivastava, S.; Ross, L. J.; Suling, W. J.; White, E. L.; Woolhiser, L. K.; Lenaerts, A. J.; Reynolds, R. C. Novel pyridopyrazine and pyrimidothiazine derivatives as FtsZ inhibitors. Bioorg. Med. Chem, 2011, 19, 7120-28.
66. Zitko, J.; Paterova, P.; Kubicek, V.; Mandikova, J.; Trejtnar, F.; Kunes, J.; Dolezal, M. Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution. Bioorg. Med. Chem. Lett, 2013, 23, 476-79.
67. Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J.; Lynch, J. J.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolism-directed optimization of 3-Aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem, 2003, 46, 461-73.
68. Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E; Neumann, W. L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Design, Parallel synthesis and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem, 2003, 46, 4050-62.
69. Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton, C. L.; Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.; Stauffer, K. J.; Vacca, J. P.; Williams, P. D.; Bohn, D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C.; Lewis, S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.; Pietrak, B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan, Y.; Nantermet, P. G. Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors. J. Med. Chem, 2004, 47, 2995-08.
70. Cheng, X.-C.; Liu, X.-Y.; Xu, W.-F.; Guo, X.-L.; Zhang, N.; Song, Y.-N. Ligustrazine derivatives. Part 3: Design, synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents. Biorg. Med. Chem, 2009, 17, 3018-24.
71. Chen, H.; Li, G.; Zhan, P.; Liu, X. Ligustrazine derivatives. Part 5: Design, synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents. Eur. J. Med. Chem, 2011, 46, 5609-15.
72. Vale, W.; Spiess, J.; Rivier, C.; Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 1981, 213, 1394-97.
73. Dzierba, C. D.; Takvorian, A. G.; Rafalski, M.; Kasireddy-Polam, P.; Wong, H.; Molski, T. F.; Zhang, G.; Li, Y. W.; Lelas, S.; Peng, Y.; McElroy, J. F.; Zaczek, R. C.; Taub, R. A.; Combs, A. P.; Gilligan, P. J.; Trainor, G. L. Synthesis, structure-activity relationships, and in vivo properties of 3, 4-Dihydro-1H-pyrido[2, 3-b]pyrazin-2-ones as corticotrophin releasing factor-1 receptor antagonists. J. Med. Chem, 2004, 47, 5783-90.
74. Corbett, J. W.; Rauckhorst, M. R.; Qian F.; Hoffman, R. L.; Knauera, C. S.; Fitzgeralda, L. W. Heteroatom-linked indanylpyrazines are corticotrophin releasing factor type-1 receptor antagonists. Bioorg. Med. Chem. Lett, 2007, 17, 6250-56.
75. 3-phenylpyrazinones as novel corticotropin-releasing Factor-1 (CRF1) receptor antagonists. J. Med. Chem., 2009, 52, 4173-91.
76. Hartz, R. A.; Ahuja, V. T.; Schmitz, W. D.; Molski, T. F.; Mattson, G. K.; Lodge, N. J.; Bronson, J. J.; Macor, J. E.; Synthesis and structure-activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Bioorg. Med. Chem. Lett, 2010, 20, 1890-94.
77. Hodgetts, K. J.; Ge, P.; Yoon, T.; Lombaert S. D.; Brodeck, R.; Gulianello, M.; Kieltyka, A.; Hoevath, R. F.; Kehne, J. H.; Krause, J. E.; Maynard, G. D.; Hoffman, D.; Lee, Y.; Fung, L.; Doller, D. Discovery of N-(1-Ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): An orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist. J. Med. Chem, 2011, 54, 4187-06.
78. Scott, L. V.; Dinan, T. G. Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression. Life Sci, 1998, 62(22), 1985-98.
79. Aguilera, G.; Rabadan-Diehl, C. Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications for stress adaptation. Regul. Pept, 2000, 96, 23-29.
80. Arban, R.; Bianchi, F.; Buson, A.; Cremonesi, S.; Fabio, R. D.; Gentile, G.; Micheli, F.; Pasquarello, A.; Pozzan, A.; Tarsi, L.; Terreni, S.; Tonelli, F. Pyrrolo[1, 2-a]pyrazine and pyrazolo[1, 5-a]pyrazine: Novel, potent, and selective series of vasopressin1b receptor antagonists. Bioorg. Med. Chem. Lett, 2010, 20, 5044-49.
81. Gullam, J. E.; Chatterjee, J.; Thornton, S. Preterm labour: Novel treatments. Drug Discovery Today: Ther. Strateg, 2005, 2, 47-52.
82. Tiwari, A., Nanda, K., Chugh, A., Benign prostatic hyperplasia: an insight into current investigational medical therapies. Expert Opin. Investig. Drugs, 2005, 14, 1359-72.
83. Brown, A.; Brown, L.; Ellis, D.; Puhalo, N.; Smith, C. R.; Wallace, O.; Watson, L. Design and optimization of potent, selective antagonists of Oxytocin. Bioorg. Med. Chem. Lett, 2008, 18, 4278-81.
84. Brown, A.; Ellis, D.; Pearce, D.; Ralph, M.; Sciammetta, N.; Aryloxypyrazines as highly selective antagonists of oxytocin. Bioorg. Med. Chem. Lett, 2009, 19, 2634-36.
85. Heeres, J.; Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinke, M.; Van Aken, K. J. A.; Arnold, E.; Das, K.; Kilonda, A.; Hoornaert, G. J.; Compernolle, F.; Cegla, M.; Azzam, R. A.; Andries, K.; Bethune, M. P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Janssen, P. A. J. Design, synthesis, and SAR of a novel pyrazinone series with non-nucleoside HIV-1 reverse transcriptase inhibitory activity. J. Med. Chem, 2005, 48, 1910-18.
86. Parsons, M. E.; Keeling, D. J. Novel approaches to the pharmacological blockade of gastric acid secretion. Expert Opin. Invest. Drugs, 2005, 14, 411-21.
87. Fass, R.; Shapiro, M.; Dekel, R.; Sewell, J. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease--where next? Aliment. Pharmacol. Ther. 2005, 22, 79-94.
88. Vakil, N. Review article: new pharmacological agents for the treatment of gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther, 2004, 19, 1041-49.
89. Andersson, K.; Carlsson, E. Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases E. Pharmacol. Ther, 2005, 108, 294-07.
90. Zimmermann, P. J.; Brehm, C.; Buhr, W.; Palmer, A. M.; Volz, J.; Simon, W. A. Novel imidazo[1, 2-a]pyrazine derivatives as potent reversible inhibitors of the gastric H+/K+-ATPase. Bioorg. Med. Chem, 2008, 16, 536-41.
91. Susa, M.; Greeen, J.; Missbach, M. Src inhibitors: drugs for the treatment of osteoporosis, cancer or both? Trends in Pharmacol. Sci, 2000, 21, 489-95.
92. Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Ozawa, T.; Kamada, N.; Komatsu, Y.; Kikuchi, S.; Oonota, H.; Kusama, H. Synthesis and c-Src inhibitory activity of imidazo[1, 5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke. Bioorg. Med. Chem, 2007, 15, 868-85.
93. Tessari, M.; Pilla, M.; Andreoli, M.; Hutcheson, D. M.; Heidbreder, C. A. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine-and cocaine-taking behaviours and prevents nicotinetriggered relapse to nicotine-seeking. Eur. J. Pharmacol, 2004, 499, 121-33.
94. Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.; Anderson, J. J.; Bristow, L.; Brodkin, J.; Jiang, X. H.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A. 3-[(2-Methyl-1, 3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J. Med. Chem, 2003, 46, 204-06.
95. Simenon, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis, R. B.; Pike, V. W. J. Synthesis and simple 18F-labeling of 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a high affinity radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with positron emission tomography. J. Med. Chem, 2007, 50, 3256-66.
96. Micheli, F.; Bertani, B.; Bozzoli, A.; Crippa, L.; Cavanni, P.; Fabio, R. D.; Donati, D.; Marzorati, P.; Merlo, G.; Paio, A.; Perugini, L.; Zarantonello, P. Phenylethynyl-pyrrolo[1, 2-a]pyrazine: A new potent and selective tool in the mGluR5 antagonists arena. Bioorg. Med. Chem. Lett, 2008, 18, 1804-09.
97. Coskran, T. M.; Morton, D.; Menniti, F. S.; Adamowicz, W. O.; Kleiman, R. J.; Ryan, A. M.; Strick, C. A.; Schmidt, C. J.; Stephenson, D. T. Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J. Histochem. Cytochem,. 2006, 54, 1205-13.
98. Seeger, T. F.; Bartlett, B.; Coskran, T. M.; Culp, J. S.; James, L. C.; Krull, D. L.; Lanfear, J.; Ryan, A. M.; Schmidt, C. J.; Strick, C. A.; Varghese, A. H.; Williams, R. D.; Wylie, P. G.; Menniti, F. S. Immunohistochemical localization of PDE10A in the rat brain. Brain Res, 2003, 985, 113-26.
99. Hofgen, N.; Stange, H.; Schindler, R.; Lankau, H. J.; Grunwald, C.; Langen, B.; Egerland, U.; Tremmel, P.; Pangalos, M. N.; Marquis, K. L.; Hage, T.; Harrison, B. L.; Malamas, M. S.; Brandon, N. J.; Kronbach, T. Discovery of Imidazo[1, 5-a]pyrido[3, 2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors. J. Med. Chem, 2010, 53, 4399-11.
100. Lapiz, M. D.; Fulford, A.; Muchimapura, S.; Mason, R.; Parker, T.; Marsden, C. A. Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. Neurosci. Behav. Physiol, 2003, 33, 13-29.
101. Scanio, M. J. C.; Lei Shi L.; Drizin, I.; Gregg, R. J.; Atkinson, R. N.; Thomas, J. B.; Johnson, M. S.; Chapman, M. L.; Liu, D.; Krambis, M. J.; Liu, Y.; Shieh, C. C.; Zhang, X.; Simler, G. H.; Joshi, S.; Honore, P.; Marsh, K. C.; Knox, A.; Werness, S.; Antonio, B.; Krafte, D. S.; Jarvis, M. F.; Faltynek, C. R.; Marron, B. E.; Kort, M. E. Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1. 8 sodium channel with efficacy in a model of neuropathic pain. Bioorg. Med. Chem, 2010, 18, 7816-25.
102. Hirsh, A. J.; Molino, B. F.; Zhang, J.; Astakhova, N.; Geiss, W. B.; Sargent, B. J.; Swenson, B. D.; Usyatinsky, A.; Wyle, M. J.; Boucher, R. C.; Smith, R. T.; Zamurs, A.; Johnson, M. R. Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: Drugs for cystic fibrosis and chronic bronchitis. J. Med. Chem, 2006, 49, 4098-15.
103. Lemaître, S.; Lepailleur, A.; Bureau, R.; Butt-Gueulle, S.; Lelong-Boulouard, V.; Duchatelle, P.; Boulouard, M.; Dumuis, A.; Daveu, C.; Lezoualch, F.; Pfeiffer, B.; Dauphin, F.; Rault, S. Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines. Bioorg. Med. Chem, 2009, 17, 2607-22.
104. n]-2(1H)-pyrazinone with central-mediated analgesia, J. Med. Chem, 2004, 47, 2599-10.
105. Mócsai, A.; Ruland, J.; Tybulewicz, V. L. J. The Syk tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol, 2010, 10, 387-02.
106. Forns, P.; Esteve, C.; taboada, L.; Alonso, J. A.; Orellana, A.; Maldonado, M.; Carreno, C.; Ramis, I.; Miralpeix, M. Pyrazinebased Syk kinase inhibitors. Bioorg. Med. Chem. Lett, 2012, 22, 2784-88.
107. Krishna, M. C.; De Graff, W.; Hankovzsky, O. H.; Sar, C. P.; Kalai, T.; Jeko, J.; Russo, A.; Mitchell, J. B.; Hideg, K. Studies of structure-activity relationship of nitroxide free radicals and their precursors as modifiers against oxidative damage. J. Med. Chem, 1998, 41, 3477-92.
108. Schackelfold, R. E.; Kaufmann, W. K.; Paules, R. S. Oxidative stress and cell cycle checkpoint function. Free Rad. And Biol. Med, 2000, 28, 1387.
109. Kehrer, J. P. The haber-Weiss reaction and mechanism of toxicity. Toxicology, 2000, 149, 43-50.
110. Rees, J.-F.; De Wergifosse, B.; Noiset, O.; Dubuisson, M.; Janssens, B.; Thompson, E. M. The origins of marine bioluminescence: turning oxygen defence mechanism in to deepsea communication tools. J. exp. Biol, 1998, 201, 1211-21.
111. Dubuisson, M. L. N.; De Wergifosse, B.; Trouet, A.; Baguet,-F.; Marchand-Brynaert, J.; Rees, J. F. antioxidative properties of natural coelenterazine and synthetic methyl coelenterazine in rat hepatocytes subjected to ter. butyl hydroperoxide induced oxidative stress. Biochem. Pharmacol, 2000, 60, 471-78.
112. Devillers, I.; Dive, G.; De Tollenaere, C.; Falmagne, B.; De Wergifosse, B.; Rees, J.-F.; Marchand-brynaert, J. Imidazolopyrazinones as a potential antioxidants. Bioorg. Med. Chem. Lett, 2001, 11, 2305-09.
113. Dubuisson, M. L. N.; Rees, J.-F.; Marchand-brynaert, J. Discovery and validation of a new family of antioxidants: the aminopyrazine derivatives. Mini-reviews in medicinal chemistry, 2004, 4, 159-65.
114. Christie, A. W.; Mccormick, D. K.; Emmison, N.; Kraemer, F. B.; Alberti, K. G.; Yeaman S. J. Mechanism of anti-lipolytic action of Acipimox in isolated rat adipocytes. Diabetologia, 1996, 39, 45-53.
115. Loffing, J.; Kaissling, B. Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human. Am. J. Physiol. Renal. Physiol, 2003, 284, 628-43.
116. + channels from M-1 cortical collecting duct cells. Am. J. Physiol. Renal. Fluid Electrolyte Physiol, 1995, 271, 861-70.
117. Prendergast, B. D. Glyburide and Glipizide, second-generation oral sulfonylurea hypoglycaemic agents. Clin. Pharm, 1984, 3, 473-85.
118. Bonanni, G.; Ciccariello, M.; Mancini, P. P. V.; Sagliaschi, G. Concomitant ceco-appendicular and urinary tuberculosis. Description of two rare cases: physiopathological and diagnostic remarks. Riv Eur Sci Med Farmacol, 1993, 15, 171-74.
119. Zimhony, O.; Cox, J. S.; Welch, J. T.; Vilchèze, C.; Jacobs, W. R. Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FAS-I) of Mycobacterium tuberculosis. Nat. Med, 2000, 6, 1043-47.
120. Iida, K.; Itoh, K.; Kumagai Y. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res, 2004, 64, 6424-31.
121. Barth, F. CB1 Cannabinoid Receptor Antagonists. Annu. Rep. Med. Chem, 2005, 40, 103-18.
122. Revill, P.; Serradell, N.; Bolos, J.; Rosa, E. Telaprevir. Drugs Fut, 2007, 32, 788-98.
123. Mills, E. J.; Wu, P.; Spurden, D.; Ebbert, J. O.; Wilson, K. Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis. Harm Reduct J, 2009, 6, 25.
124. James, N. D.; Growcott, J. W. Zibotentan. Drugs Fut, 2009, 34, 624-33.