HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase

Bioorganic and Medicinal Chemistry Letters

Volumn 24, Issue 5, 2014, Pages 1315-1321

  Evenäs, Johan ^a   Edfeldt, Fredrik ^a   Lepistö, Matti ^a   Svitacheva, Naila ^a   Synnergren, Anna ^a   Lundquist, Britta ^a   Gränse, Mia ^a   Rönnholm, Anna ^a   Varga, Mikael ^a   Wright, John ^b   Wei, Min ^b   Yue, Sherrie ^b   Wang, Junfeng ^b   Li, Chong ^b   Li, Xuan ^b   Chen, Gang ^b   Liao, Yong ^b   Lv, Gang ^a   Tjörnebo, Ann ^a   Narjes, Frank ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b BioDuro   (China)

Author keywords

High throughput screening; Hit to lead; Non purine XO inhibitors; Pyrimidone; Xanthine oxidase

Indexed keywords

HIGH-THROUGHPUT SCREENING; HIT-TO-LEAD; NON-PURINE XO INHIBITORS; PYRIMIDONE; XANTHINE OXIDASE;

ANIMALS; BINDING SITES; DRUG EVALUATION, PRECLINICAL; ENZYME ACTIVATION; ENZYME INHIBITORS; GOUT SUPPRESSANTS; HALF-LIFE; HIGH-THROUGHPUT SCREENING ASSAYS; HYPERURICEMIA; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR DOCKING SIMULATION; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PYRIMIDINONES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; XANTHINE OXIDASE;

EID: 84894572482     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2014.01.050     Document Type: Article

References (35)

1. F. Borges, E. Fernandes, and F. Roleira Curr. Med. Chem. 9 2002 195
2. P. Pacher, A. Nivorozhkin, and C. Szab Pharmacol. Rev. 58 2006 87
3. R. Harrison Drug Metab. Rev. 36 2004 363
4. A. Bouez, M. Damarla, and P.M.A. Hassoun Am. J. Physiol. Lung Cell. Mol. Physiol. 294 2008 830
5. B.S. Kim, L. Serebreni, O. Hamdan, L. Lan Wang, A. Parniani, T. Sussan, R.S. Stephens, L. Boyer, M. Damarla, P.M. Hassoun, and R. Damico Free Radical Biol. Med. 60 2013 336
6. V. Massey, H. Komani, G. Palmer, and G.B. Elion J. Biol. Chem. 245 1970 2837
7. K. Okamoto, B.T. Eger, T. Nishino, E.F. Pai, and T. Nishino Nucleosides, Nucleotides Nucleic Acids 27 2008 888
8. L.A. Sorbera, L. Revel, X. Rabasseda, and J. Castaner Drugs Future 26 2001 32
9. S. Ishibuchi, H. Morimoto, T. Oe, T. Ikebe, H. Inoue, A. Fukunari, M. Kamezawa, I. Yamada, and Y. Naka Bioorg. Med. Chem. Lett. 11 2001 879
10. K. Matsumoto, K. Okamoto, N. Ashizawa, and T. Nishino J. Pharmacol. Exp. Ther. 336 2011 95
11. C. B-Rao, A. Kulkarni-Almeida, K.V. Katkar, S. Khanna, U. Ghosh, A. Keche, P. Shah, A. Srivastava, V. Korde, K.V.S. Nemmani, N.J. Deshmuk, A. Dixit, M.K. Brahma, U. Bahirat, L. Doshi, R. Sharma, and H. Sivaramakrishnan Bioorg. Med. Chem. 20 2012 2930
12. S. Khanna, S. Burudkar, K. Bajaj, P. Shah, A. Keche, U. Ghosh, A. Desai, A. Srivastava, A. Kulkarni-Almeida, N.J. Deshmukh, A. Dixit, M.K. Brahma, U. Bahirat, L. Doshi, K.V. Nemmani, P. Tannu, A. Damre, C. B-Rao, R. Sharma, and H. Sivaramakrishnan Bioorg. Med. Chem. Lett. 22 2012 7543
13. K. Bajaj, S. Burudkar, P. Shah, A. Keche, U. Ghosh, P. Tannu, S. Khanna, A. Srivastava, N.J. Deshmukh, A. Dixit, Y. Ahire, A. Damre, K.V.S. Nemmani, A. Kulkarni-Almeida, C. B-Rao, R. Sharm, and H. Sivaramakrishnan Bioorg. Med. Chem. Lett. 23 2013 834
14. K.R. Sathisha, S.A. Khanum, J.N.N.S. Chandra, F. Ayisha, S. Balaji, G.K. Mrathe, S. Gopal, and K.S. Rangappa Bioorg. Med. Chem. Lett. 22 2012 7543
15. M. Leigh, D.J. Raines, C.E. Castillo, and A.K. Duhme-Klair ChemMedChem 6 2011 1107
16. L. Hu, H. Hu, W. Wu, X. Chai, J. Luo, and Q. Wu Bioorg. Med. Chem. Lett. 21 2011 4013
17. K. Nepali, A. Agarwal, S. Sapra, V. Mittal, R. Kumar, U.C. Banerjee, M.K. Gupta, N.K. Satti, O.P. Suri, and K.L. Dhar Bioorg. Med. Chem. Lett. 19 2011 5569
18. 50 determinations C-terminally FLAG tagged human Xanthine Oxidase (aa 1-1333) was used. hXO was overexpressed using the Bac-to-Bac Baculo Virus expression system in High Five cells (Life Technologies) and purified by a combination of FLAG gel capture and size exclusion chromatography into the buffer 50 mM Tris-HCl pH 7.6, 0.1 M NaCl. To a 384 well plate, containing a solution of human XO (9.5 μL, 105 nmol in 0.1 M Tris-HCl, pH 7.5), were added test compounds (0.5 μL, 10 mM in DMSO) at different concentrations. After incubation at rt for 15 min, 10 μL of a solution of Xanthine (200 μM in 0.1 M Tris HCl, pH 7.5) was added. The reaction was allowed to run for 60 min at RT, then Quantichrom reagent (20 μL, BioAssay Systems, USA: http://www.bioassaysys.com/file-dir/DIUA.pdf) was added and the plate incubated for 30 min. The absorbance was measured at 590 nm using a SpectraMax 384 reader.
19. R. Sink, S. Gobec, S. Pecar, and A. Zega Curr. Med. Chem. 17 2010 4231
20. P.J. Hajduk, E.T. Olejniczak, and S.W. Fesik J. Am. Chem. Soc. 119 1996 12257
21. C. Dalvit, M. Flocco, S. Knapp, M. Mostardini, R. Perego, B.J. Stockman, M. Veronesi, and M. Varasi J. Am. Chem. Soc. 124 2002 7002
22. W. Jahnke, P. Floersheim, C. Ostermeier, X. Zhang, R. Hemmig, K. Hurth, and D. Uzunov Angew. Chem., Int. Ed. 41 2002 3420
23. C. Enroth, B.T. Eger, K. Okamoto, T. Nishino, T. Nishino, and E.F. Pai Proc. Natl. Acad. Sci. U.S.A. 97 2000 10723
24. M.D. Shultz Bioorg. Med. Chem. Lett. 23 2013 5992
25. E. Perola J. Med. Chem. 53 2010 2986
26. P.D. Leeson, and B. Springthorpe Nat. Rev. Drug Disc. 6 2007 881
27. K. Okamoto, B.T. Eger, T. Nishino, S. Kondo, E.F. Pai, and T. Nishino J. Biol. Chem. 278 2003 1848
28. Details on model construction, docking and coordinates of selected molecules can be found in the supplementary material.
29. D.F. McGinnity, A.J. Parker, M. Soars, and R.J. Riley Drug Metab. Dispos. 28 2000 1327
30. M.T. Nguyen, and S. Awale Biol. Pharm. Bull. 2005 2231
31. P. Arturson, and J. Karlsson Biochem. Biophys. Res. Commun. 175 1991 880
32. H.I. Skulnick, J.H. Ludens, M.G. Wendling, E.M. Glenn, N.A. Rohloff, R.J. Smith, and W. Wierenga J. Med. Chem. 29 1986 1499
33. H.I. Skulnick, S.D. Weed, E.E. Eidson, H.E. Renis, D.A. Stringfellow, and W. Wierenga J. Med. Chem. 28 1985 1846
34. M. Bararjanian, S. Balalaie, S. Barouti, and F. Rominger Helv. Chim. Acta 93 2010 777
35. D.R. Hannah, E.C. Sherer, R.V. Davies, R.B. Titman, C.A. Laughton, and M.F.G. Stevens Bioorg. Med. Chem. 8 2000 739