Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 22, 2012, Pages 6811-6816

  Heasley, Brian H ^a   Pacofsky, Gregory J ^a   Mamai, Ahmed ^a   Liu, Hao ^a   Nelson, Kingsley ^a   Coti, Ghjuvanni ^a   Peel, Michael R ^a   Balkovec, James M ^b   Greenlee, Mark L ^b   Liberator, Paul ^b   Meng, Dongfang ^b   Parker, Dann L ^b   Wilkening, Robert R ^b   Apgar, James M ^b   Racine, F ^b   Hsu, Ming Jo ^b   Giacobbe, Robert A ^b   Kahn, Jennifer Nielsen ^b  

^a SCYNEXIS Inc   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

1,3 Glucan synthase; Antifungal agents; Enfumafungin; Medicinal chemistry; Oral bioavailability; Triterpenoid glycoside

Indexed keywords

1,3 BETA GLUCAN SYNTHASE; ANTIFUNGAL AGENT; ENFUMAFUNGIN; GLYCOSIDE; NITROGEN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DEMETHYLATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; MALE; MOUSE; NONHUMAN;

ADMINISTRATION, ORAL; ANIMALS; ANTIFUNGAL AGENTS; CANDIDA ALBICANS; ENZYME INHIBITORS; GLUCOSYLTRANSFERASES; GLYCOSIDES; HALF-LIFE; MICE; STRUCTURE-ACTIVITY RELATIONSHIP; TRITERPENES;

EID: 84867882342     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.05.031     Document Type: Article

References (21)

1. B.H. Heasley Angew. Chem.; Int. Ed. 50 2011 8474 and references cited therein
2. F.C. Odds, A.J.P. Brown, and N.A.R. Gow Trends Microbiol. 11 2003 272
3. M.A. Ghannoum, and L.B. Rice Clin. Microbiol. Rev. 12 1999 501
4. E.D. Brown, and G.D. Wright Chem. Rev. 105 2005 759
5. M.F. Vicente, A. Basilio, A. Cabello, and F. Pelaez Clin. Microbiol. Infect. 9 2003 15
6. http://www.merck.com/licensing/news-and-events/scynexis-press-release. html.
7. F.A. Bouffard, R.A. Zambias, J.F. Dropinski, J.M. Balkovec, M.L. Hammond, G.K. Abruzzo, K.F. Bartizal, J.A. Marrinan, M.B. Kurtz, D.C. McFadden, K.H. Nollstadt, M.A. Powles, and D.M. Schmatz J. Med. Chem. 37 1994 222
8. J.M. Balkovec, R.M. Black, M.L. Hammond, J.V. Heck, R.A. Zambias, G. Abruzzo, K. Bartizal, H. Kropp, C. Trainor, R.E. Schwartz, D.C. McFadden, K.H. Nollstadt, L.A. Pittaressi, M.A. Powles, and D.M. Schmatz J. Med. Chem. 35 1992 194
9. W.R. Leonard, K.M. Belyk, D.A. Conlon, D.R. Bender, L.M. DiMichele, J. Liu, and D.L. Hughes J. Org. Chem. 72 2007 2335
10. The %F of caspofungin acetate in mice is approximately 0.3-1%: G.K. Abruzzo, A.M. Flattery, C.J. Gill, L. Kong, J.G. Smith, V.B. Pikounis, J.M. Balkovec, F.A. Bouffard, J.F. Dropinski, H. Rosen, H. Kropp, and K. Bartizal Antimicrob. Agents Chemother. 41 1997 2333
11. J. Onishi, M. Meinz, J. Thompson, J. Curotto, S. Dreikorn, M. Rosenbach, C. Douglas, G. Abruzzo, A. Flattery, L. Kong, A. Cabello, F. Vicente, F. Pelaez, M.T. Diez, I. Martin, G. Bills, R. Giacobbe, A. Dombrowski, R. Schwartz, S. Morris, G. Harris, A. Tsipouras, K. Wilson, and M.B. Kurtz Antimicrob. Agents Chemother. 44 2000 368
12. R.E. Schwartz, S.K. Smith, J.C. Onishi, M. Meinz, M. Kurtz, R.A. Giacobbe, K.E. Wilson, J. Liesch, D. Zink, W. Horn, S. Morris, A. Cabello, and F. Vicente J. Am. Chem. Soc. 122 2000 4882
13. Balkovec, J. M.; Bouffard, F. A.; Tse, B.; Dropinski, J.; Meng, D.; Greenlee, M. L.; Peel, M. R.; Fan, W.; Mamai, A.; Liu, H.; Li, K. PCT International Patent Application, WO 2007127012 A1, 2007.
14. Balkovec, J. M.; Siliphaivanh, P.; Bouffard, F. A.; Peel, M. R.; Fan, W.; Mamai, A.; Dimick Gray, S. M. PCT International Patent Application, WO 2009045311 A1, 2009.
15. Peel, M. R.; Mamai, A.; Fan, W.; Dimick-Gray, S.; Hong, J.; Orr, M. D.; Balkovec, J. M.; Greenlee, M. L.; Waddell, S.; Abruzzo, G. Flattery, A.; Giacobbe, R.; Gill, C.; Hsu, M.-J.; Racine, F.; Liberator, P.; Nielsen Kahn, J. Poster F1-848 ICAAC 2010.
16. Greenlee, M. L.; Wilkening, R.; Apgar, J.; Sperbeck, D.; Wildonger, K. J.; Meng, D.; Parker, D. L.; Pacofsky, G. J.; Heasley, B. H.; Mamai, A.; Nelson, K. PCT International Patent Application, WO 2010019204 A1, 2010.
17. Wilkening, R.; Apgar, J.; Meng, D.; Parker, D. L.; Greenlee, M. L.; Sperbeck, D.; Wildonger, K. J.; Abruzzo, G.; Flattery, A.; Galgoci, A.; Giacobbe, R.; Gill, C.; Hsu, M.-J.; Liberator, P.; Misura, A.; Motyl, M.; Nielsen Kahn, J.; Powles, M. A.; Racine, F.; Dragovic, J.; Habulihaz, B.; Fabre, E.; Heasley, B. H.; Kirwan, R.; Lee, S.; Liu, H.; Mamai, A.; Nelson, K.; Pacofsky, G. J.; Peel, M. R.; Balkovec, J. M. Poster F1-846 ICAAC, 2010.
18. T. Kawabata, K. Moriyama, S. Kawakami, and K. Tsubaki J. Am. Chem. Soc. 130 2008 4153
19. T. Kawabata, S. Kawakami, and S. Majumdar J. Am. Chem. Soc. 125 2003 13012
20. S. Xu, B. Zhu, Y. Teffera, D.E. Pan, C.G. Caldwell, G. Doss, R.A. Stearns, D.C. Evans, and M.G. Beconi Drug Metab. Dispos. 33 2005 121
21. H. McKennis, S.L. Schwartz, and E.R. Bowman J. Biol. Chem. 239 1964 3990