Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile

Journal of Medicinal Chemistry

Volumn 58, Issue 2, 2015, Pages 927-942

  Surivet, Jean Philippe ^a   Zumbrunn, Cornelia ^a   Rueedi, Georg ^a   Bur, Daniel ^a   Bruyère, Thierry ^a   Locher, Hans ^a   Ritz, Daniel ^a   Seiler, Peter ^a   Kohl, Christopher ^a   Ertel, Eric A ^a   Hess, Patrick ^a   Gauvin, Jean Christophe ^a   Mirre, Azely ^a   Kaegi, Verena ^a   Dos Santos, Marina ^a   Kraemer, Stéphanie ^a   Gaertner, Mika ^a   Delers, Jonathan ^a   Enderlin Paput, Michel ^a   Weiss, Maria ^a   Sube, Romain ^a   Hadana, Hakim ^a   Keck, Wolfgang ^a   Hubschwerlen, Christian ^a   more..

^a ACTELION PHARMACEUTICALS LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

1 (5 AMINO TETRAHYDRO PYRAN 2 YL) 2 (6 METHOXY[1,5]NAPHTHYRIDIN 4 YL)ETHANOL; 1 (5 AMINOTETRAHYDRO 2H PYRAN 2 YL) 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 1 [5 [[(2,3 DIHYDRO[1,4]DIOXINO[2,3 C]PYRIDIN 7 YL)METHYL]AMINO]TETRAHYDRO 2H PYRAN 2 YL] 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 1 [5 [[(2,3 DIHYDRO[1,4]OXATHIINO[2,3 C]PYRIDIN 7 YL)METHYL]AMINO]TETRAHYDRO 2H PYRAN 2 YL] 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 1 [5 [[(6,7 DIHYDRO[1,4]DIOXINO[2,3 C]PYRIDAZIN 3 YL)METHYL]AMINO]TETRAHYDRO 2H PYRAN 2 YL] 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 1 [5 [[(6,7 DIHYDRO[1,4]OXATHIINO[2,3 C]PYRIDAZIN 3 YL)METHYL]AMINO]TETRAHYDRO 2H PYRAN 2 YL] 2 (3 FLUORO 6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 1 [5 [[(6,7 DIHYDRO[1,4]OXATHIINO[2,3 C]PYRIDAZIN 3 YL)METHYL]AMINO]TETRAHYDRO 2H PYRAN 2 YL] 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHAN 1 OL; 6 [[[6 [1 HYDROXY 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHYL]TETRAHYDRO 2H PYRAN 3 YL]AMINO]METHYL] 2H PYRIDO[ 3,2 B][1,4]OXAZIN 3(4H)ONE; 6 [[[6 [1 HYDROXY 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHYL]TETRAHYDRO 2H PYRAN 3 YL]AMINO]METHYL] 2H PYRIDO[3,2 B][1,4]THIAZIN 3(4H)ONE; ANTIBIOTIC AGENT; CIPROFLOXACIN; DNA TOPOISOMERASE (ATP HYDROLYSING); DNA TOPOISOMERASE INHIBITOR; GYRASE INHIBITOR; LINEZOLID; POTASSIUM CHANNEL HERG; TERT BUTYL [6 [(6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHYNYL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [1 HYDROXY 2 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL)ETHYL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [2 (3 FLUORO 6 METHOXY 1,5 NAPHTHYRIDIN 4 YL) 1 HYDROXYETHYL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [2 (6 FLUORO 3 METHOXYQUINOXALIN 5 YL) 1 HYDROXYETHYL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [2 (7 FLUORO 2 METHOXYQUINOLIN 8 YL) 1 HYDROXYETHYL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [5 (3 FLUORO 6 METHOXY 1,5 NAPHTHYRIDIN 4 YL) 2 OXO 1,3 DIOXOLAN 4 YL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [5 (6 FLUORO 3 METHOXYQUINOXALIN 5 YL) 2 OXO 1,3 DIOXOLAN 4 YL]TETRAHYDRO 2H PYRAN 3 YL] CARBAMATE; TERT BUTYL [6 [5 (6 METHOXY 1,5 NAPHTHYRIDIN 4 YL) 2 OXO 1,3 DIOXOLAN 4 YL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TERT BUTYL [6 [5 (7 FLUORO 2 METHOXYQUINOLIN 8 YL) 2 OXO 1,3 DIOXOLAN 4 YL]TETRAHYDRO 2H PYRAN 3 YL]CARBAMATE; TETRAHYDROPYRAN DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; [6 (6 METHOXY[1,5]NAPHTHYRIDIN 4 YLETHYNYL)TETRAHYDRO PYRAN 3 YL]CARBAMIC ACID BENZYL ESTER; [6 [1 HYDROXY 2 (6 METHOXY[1,5]NAPHTHYRIDIN 4 YL)ETHYL]TETRAHYDRO PYRAN 3 YL]CARBAMIC ACID BENZYL ESTER; [6 [2 (6 METHOXY[1,5]NAPHTHYRIDIN 4 YL)ACETYL]TETRAHYDRO PYRAN 3 YL]CARBAMIC ACID BENZYL ESTER; ANTIINFECTIVE AGENT; PYRAN DERIVATIVE;

ACINETOBACTER BAUMANNII; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; AREA UNDER THE CURVE; ARTICLE; CARDIOVASCULAR FUNCTION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; DRUG SYNTHESIS; ENTEROCOCCUS FAECALIS; ENTEROCOCCUS FAECIUM; ENZYME ACTIVITY; ENZYME INHIBITION; ESCHERICHIA COLI; EXPERIMENTAL DOG; FEMALE; GRAM POSITIVE BACTERIUM; GUINEA PIG; HAEMOPHILUS INFLUENZAE; HEART RATE; IC50; IN VITRO STUDY; IN VIVO STUDY; MALE; MEAN ARTERIAL PRESSURE; MINIMUM BACTERICIDAL CONCENTRATION; MINIMUM INHIBITORY CONCENTRATION; MORAXELLA CATARRHALIS; MOUSE; NONHUMAN; QT INTERVAL; RAT; STAPHYLOCOCCUS AUREUS; STAPHYLOCOCCUS EPIDERMIDIS; STREPTOCOCCUS AGALACTIAE; STREPTOCOCCUS PNEUMONIAE; STREPTOCOCCUS PYOGENES; STRUCTURE ACTIVITY RELATION; ANIMAL; DRUG EFFECTS; HEMODYNAMICS; HUMAN; MICROBIAL SENSITIVITY TEST; SYNTHESIS; WISTAR RAT;

ANIMALS; ANTI-BACTERIAL AGENTS; GRAM-POSITIVE BACTERIA; GUINEA PIGS; HEMODYNAMICS; HUMANS; MALE; MICE; MICROBIAL SENSITIVITY TESTS; PYRANS; RATS; RATS, WISTAR; STRUCTURE-ACTIVITY RELATIONSHIP; TOPOISOMERASE II INHIBITORS;

EID: 84921508915     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501590q     Document Type: Article

References (41)

1. Antibiotic Resistance Threats in the United States; Centers for Disease Control and Prevention (CDC): Atlanta, GA, 2013; http://www.cdc.gov/drugresistance/threat-report-2013/.
2. Infectious Diseases Society of America. The 10 x '20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin. Infect. Dis. 2010, 50, 1081-3.
3. Spellberg, B.; Blaser, M.; Guidos, R. J.; Boucher, H. W.; Bradley, J. S.; Eisenstein, B. I.; Gerding, D.; Lynfield, R.; Reller, L. B.; Rex, J.; Schwartz, D.; Septimus, E.; Tenover, F. C.; Gilbert, D. N. Combating antimicrobial resistance: policy recommendations to save lives Clin. Infect. Dis. 2011, 52 (Suppl 5) S397-S428
4. Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.; Scheld, M.; Spellberg, B.; Bartlett, J. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America Clin. Infect. Dis. 2009, 48, 1-12
5. Boucher, H. W.; Talbot, G. H.; Benjamin, D. K., Jr.; Bradley, J.; Guidos, R. J.; Jones, R. N.; Murray, B. E.; Bonomo, R. A.; Gilbert, D. 10 x '20 Progress-development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America Clin. Infect. Dis. 2013, 56, 1685-1694
6. East, S. P.; Silver, L. L. Multitarget ligands in antibacterial research: progress and opportunities Expert Opin. Drug Discovery 2013, 8, 143-156
7. Mayer, C.; Janin, Y. L. Non-quinolone inhibitors of bacterial type IIA topoisomerases: a feat of bioisosterism Chem. Rev. 2014, 114, 2313-2342
8. Sanyal, G.; Doig, P. Bacterial DNA replication enzymes as targets for antibacterial drug discovery Expert Opin. Drug Discovery 2012, 7, 327-339
9. Gellert, M.; Mizuuchi, K.; O'Dea, M. H.; Nash, H. A. DNA gyrase: an enzyme that introduces superhelical turns into DNA Proc. Natl. Acad. Sci. U. S. A. 1976, 73, 3872-3876
10. Kato, J.; Nishimura, Y.; Imamura, R.; Niki, H.; Hiraga, S.; Suzuki, H. New topoisomerase essential for chromosome segregation in E. coli Cell 1990, 63, 393-404
11. Mitscher, L. A. Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents Chem. Rev. 2005, 105, 559-592
12. Hoeksema, H.; Caron, E. L.; Hinman, J. W. Novobiocin. III. The structure of novobiocin. J. Am. Chem. Soc. 1956, 78.
13. Smith, D. H.; Davis, B. D. Mode of action of novobiocin in Escherichia coli J. Bacteriol. 1967, 93, 71-79
14. Shen, L. L.; Mitscher, L. A.; Sharma, P. N.; O'Donnell, T. J.; Chu, D. W.; Cooper, C. S.; Rosen, T.; Pernet, A. G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug-DNA binding model Biochemistry 1989, 28, 3886-3894
15. Jacoby, G. A. Mechanisms of resistance to quinolones Clin. Infect. Dis. 2005, 41, S120-S126
16. Tanaka, M.; Wang, T.; Onodera, Y.; Uchida, Y.; Sato, K. Mechanism of quinolone resistance in Staphylococcus aureus J. Infect. Chemother. 2000, 6, 131-139
17. Drlica, K.; Zhao, X. DNA gyrase, topoisomerase IV, and the 4-quinolones Microbiol. Mol. Biol. Rev. 1997, 61, 377-392
18. Coates, W. J.; Gwynn, M. N.; Hatton, I. K.; Masters, P. J.; Pearson, N. D.; Rahman, S. S.; Slocombe, B.; Warrack, J. D. Quinoline derivatives as antibacterials. WO 99376635, 1999.
19. Malleron, J.-L.; Tabart, M.; Carry, J. C.; Evers, M.; El Ahmad, Y.; Mignani, S.; Viviani, F. Quinolyl propyl piperidine derivatives and their use as antibacterial agents. WO 200125227, 2001.
20. Miles, T. J.; Axten, J. M.; Barfoot, C.; Brooks, G.; Brown, P.; Chen, D.; Dabbs, S.; Davies, D. T.; Downie, D. L.; Eyrisch, S.; Gallagher, T.; Giordano, I.; Gwynn, M. N.; Hennessy, A.; Hoover, J.; Huang, J.; Jones, G.; Markwell, R.; Miller, W. H.; Minthorn, E. A.; Rittenhouse, S.; Seefeld, M.; Pearson, N. Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases Bioorg. Med. Chem. Lett. 2011, 21, 7489-7495
21. Black, M. T.; Stachyra, T.; Platel, D.; Girard, A. M.; Claudon, M.; Bruneau, J. M.; Miossec, C. Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases Antimicrob. Agents Chemother. 2008, 52, 3339-3349
22. Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry, D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.; Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.; Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings, A.; Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Type IIA topoisomerase inhibition by a new class of antibacterial agents Nature 2010, 466, 935-940
23. Miles, T. J.; Hennessy, A. J.; Bax, B.; Brooks, G.; Brown, B. S.; Brown, P.; Cailleau, N.; Chen, D.; Dabbs, S.; Davies, D. T.; Esken, J. M.; Giordano, I.; Hoover, J. L.; Huang, J.; Jones, G. E.; Sukmar, S. K.; Spitzfaden, C.; Markwell, R. E.; Minthorn, E. A.; Rittenhouse, S.; Gwynn, M. N.; Pearson, N. D. Novel hydroxyl tricyclics (e.g. GSK966587) as potent inhibitors of bacterial type IIA topoisomerases Bioorg. Med. Chem. Lett. 2013, 23, 5437-5441
24. Black, M. T.; Coleman, K. New inhibitors of bacterial topoisomerase GyrA/ParC subunits Curr. Opin. Invest. Drugs 2009, 10, 804-810
25. Bouchillon, S. K.; Hackel, M.; Miller, L. A.; Scangarella-Oman, N. E. In vitro activity of GSK2140944, a Novel topoisomerase inhibitor, against isolates associated with lower respiratory tract and skin infections. In 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Denver, CO, September 10-13, 2013, Poster F1-1216.
26. Reck, F.; Alm, R. A.; Brassil, P.; Newman, J. V.; Ciaccio, P.; McNulty, J.; Barthlow, H.; Goteti, K.; Breen, J.; Comita-Prevoir, J.; Cronin, M.; Ehmann, D. E.; Geng, B.; Godfrey, A. A.; Fisher, S. L. Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II with reduced p K a: antibacterial agents with an improved safety profile J. Med. Chem. 2012, 55, 6916-6933
27. Hameed, P. S.; Patil, V.; Solapure, S.; Sharma, U.; Madhavapeddi, P.; Raichurkar, A.; Chinnapattu, M.; Manjrekar, P.; Shanbhag, G.; Puttur, J.; Shinde, V.; Menasinakai, S.; Rudrapatana, S.; Achar, V.; Awasthy, D.; Nandishaiah, R.; Humnabadkar, V.; Ghosh, A.; Narayan, C.; Ramya, V. K.; Kaur, P.; Sharma, S.; Werngren, J.; Hoffner, S.; Panduga, V.; Kumar, C. N.; Reddy, J.; Mahesh Kumar, K. N.; Ganguly, S.; Bharath, S.; Bheemarao, U.; Mukherjee, K.; Arora, U.; Gaonkar, S.; Coulson, M.; Waterson, D.; Sambandamurthy, V. K.; de Sousa, S. M. Novel N-Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against Mycobacterium tuberculosis J. Med. Chem. 2014, 57, 4889-4905
28. Surivet, J. P.; Zumbrunn, C.; Rueedi, G.; Hubschwerlen, C.; Bur, D.; Bruyere, T.; Locher, H.; Ritz, D.; Keck, W.; Seiler, P.; Kohl, C.; Gauvin, J. C.; Mirre, A.; Kaegi, V.; Dos Santos, M.; Gaertner, M.; Delers, J.; Enderlin-Paput, M.; Boehme, M. Design, synthesis, and characterization of novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram-positive activity J. Med. Chem. 2013, 56, 7396-7415
29. Hubschwerlen, C.; Rueedi, G.; Surivet, J. P.; Zumbrunn Acklin, C. 5-Amino-2-(2-heteroaryl-1-hydroxyethyl)tetrahydropyran derivatives. WO 2010067332, 2010.
30. Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry Chem. Rev. 2007, 107, 874-922
31. Thomas, R. J.; Campbell, K. N.; Hennion, G. F. Catalytic Hydration of Alkylacetylenes J. Am. Chem. Soc. 1938, 60, 718-720
32. Brooks, G.; Dabbs, S.; Davies, D. T.; Hennessy, A. J.; Jones, G. E.; Markwell, R. E.; Miles, T. J.; Owston, N. A.; Pearson, N. D.; Peng, T. W. The design of efficient and selective routes to pyridyl analogues of 3-oxo-3,4-dihydro-2 H -1,4-(benzothiazine or benzoxazine)-6-carbaldehydes Tetrahedron Lett. 2010, 51, 5035-5037
33. The diffraction data was deposited into the Cambridge Crystallographic Data Centre (CCDC 1022935). Information concerning the X-ray structure determination of compound 32d can be retrieved from http://www.ccdc.cam.ac.uk/.
34. Clinical Laboratory and Standards Institut. Methods for Dilution Susceptibility Test for Bacteria That Grow Aerobically, 7th ed.; Approved Standard, document. M7-A7; Clinical Laboratory and Standards Institut, Wayne, PA, 2006.
35. Salvi, V.; Karnad, D. R.; Panicker, G. K.; Kothari, S. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development Br. J. Pharmacol. 2010, 159, 34-48
36. Morissette, P.; Nishida, M.; Trepakova, E.; Imredy, J.; Lagrutta, A.; Chaves, A.; Hoagland, K.; Hoe, C. M.; Zrada, M. M.; Travis, J. J.; Zingaro, G. J.; Gerenser, P.; Friedrichs, G.; Salata, J. J. The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model J. Pharmacol. Toxicol. Methods 2013, 68, 137-149
37. Andes, D. unpublished results.
38. Singh, S. B.; Kaelin, D. E.; Wu, J.; Miesel, L.; Tan, C. M.; Meinke, P. T.; Olsen, D.; Lagrutta, A.; Bradley, P.; Lu, J.; Patel, S.; Rickert, K. W.; Smith, R. F.; Soisson, S.; Wei, C.; Fukuda, H.; Kishii, R.; Takei, M.; Fukuda, Y. Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents ACS Med. Chem. Lett. 2014, 5, 609-14
39. Abele, S.; Funel, J. A.; Schmidt, G.; Surivet, J. P. New Synthetic Intermediates for Manufacturing Antibiotics. WO 2012164498, 2012.
40. Kutchinsky, J.; Friis, S.; Asmild, M.; Taboryski, R.; Pedersen, S.; Vestergaard, R. K.; Jacobsen, R. B.; Krzywkowski, K.; Schroder, R. L.; Ljungstrom, T.; Helix, N.; Sorensen, C. B.; Bech, M.; Willumsen, N. J. Characterization of potassium channel modulators with QPatch automated patch-clamp technology: system characteristics and performance Assay Drug Dev. Technol. 2003, 1, 685-693
41. Andes, D.; Craig, W. A. Animal model pharmacokinetics and pharmacodynamics: a critical review Int. J. Antimicrob. Agents 2002, 19, 261-268.