Potent inhibitors of LpxC for the treatment of gram-negative infections

Journal of Medicinal Chemistry

Volumn 55, Issue 2, 2012, Pages 914-923

  Brown, Matthew F ^a   Reilly, Usa ^a   Abramite, Joseph A ^a   Arcari, Joel T ^a   Oliver, Robert ^a   Barham, Rose A ^a   Che, Ye ^a   Chen, Jinshan Michael ^a   Collantes, Elizabeth M ^a   Chung, Seung Won ^a   Desbonnet, Charlene ^a   Doty, Jonathan ^a   Doroski, Matthew ^a   Engtrakul, Juntyma J ^a   Harris, Thomas M ^a   Huband, Michael ^a   Knafels, John D ^a   Leach, Karen L ^a   Liu, Shenping ^a   Marfat, Anthony ^a   Marra, Andrea ^a   McElroy, Eric ^a   Melnick, Michael ^a   Menard, Carol A ^a   Montgomery, Justin I ^a   Mullins, Lisa ^a   Noe, Mark C ^a   O'Donnell, John ^a   Penzien, Joseph ^a   Plummer, Mark S ^a   Price, Loren M ^a   Shanmugasundaram, Veerabahu ^a   Thoma, Christy ^a   Uccello, Daniel P ^a   Warmus, Joseph S ^a   Wishka, Donn G ^a   more..

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIKACIN; ANTIBIOTIC AGENT; CEFEPIME; CEFTAZIDIME; CIPROFLOXACIN; COLLAGENASE 3; GELATINASE A; GELATINASE B; HYDROXAMIC ACID; INTERSTITIAL COLLAGENASE; MACROPHAGE ELASTASE; MATRILYSIN; N ACETYLGLUCOSAMINE; NEUTROPHIL COLLAGENASE; POLYMYXIN B; STROMELYSIN; STROMELYSIN 2; UDP 3 O (3 HYDROXYMYRISTOL) N ACETYLGLUCOSAMINE DEACETYLASE INHIBITOR; UNCLASSIFIED DRUG;

ACINETOBACTER BAUMANNII; ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ANTIBACTERIAL ACTIVITY; ARTICLE; BINDING SITE; CITROBACTER FREUNDII; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG EFFICACY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENTEROBACTER AEROGENES; ENZYME ACTIVITY; ESCHERICHIA COLI; GRAM NEGATIVE INFECTION; HUMAN; HUMAN TISSUE; HYDROGEN BOND; IC 50; KLEBSIELLA PNEUMONIAE; MINIMUM INHIBITORY CONCENTRATION; MOUSE; NONHUMAN; PSEUDOMONAS AERUGINOSA; PSEUDOMONAS INFECTION; RACEMIZATION; RAT; STRUCTURE ACTIVITY RELATION;

AMIDOHYDROLASES; ANIMALS; ANTI-BACTERIAL AGENTS; BIPHENYL COMPOUNDS; CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, BACTERIAL; HYDROGEN BONDING; HYDROXAMIC ACIDS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PHENYL ETHERS; PSEUDOMONAS AERUGINOSA; PSEUDOMONAS INFECTIONS; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFIDES; SULFONES;

EID: 84863012639     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2014748     Document Type: Article

References (27)

1. Boucher Helen, W.; Talbot George, H.; Bradley John, S.; Edwards John, E.; Gilbert, D.; Rice Louis, 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) 1-12
2. Devasahayam, G.; Scheld, W. M.; Hoffman, P. S. Newer antibacterial drugs for a new century Expert Opin. Invest. Drugs 2010, 19 (2) 215-234
3. Fischbach, M. A.; Walsh, C. T. Antibiotics for Emerging Pathogens Science 2009, 325 (5944) 1089-1093
4. Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery Nature Rev. Drug Discovery 2007, 6 (1) 29-40 (Pubitemid 46020284)
5. Cipolla, L.; Polissi, A.; Airoldi, C.; Gabrielli, L.; Merlo, S.; Nicotra, F. New targets for antibacterial design: Kdo biosynthesis and LPS machinery transport to the cell surface Curr. Med. Chem. 2011, 18 (6) 830-852
6. Vaara, M. Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria Antimicrob. Agents Chemother. 1993, 37 (2) 354-356 (Pubitemid 23046584)
7. Vuorio, R.; Vaara, M. The lipid A biosynthesis mutation lpxA2 of Escherichia coli results in drastic antibiotic supersusceptibility Antimicrob. Agents Chemother. 1992, 36 (4) 826-829
8. Young, K.; Silver, L. L.; Bramhill, D.; Cameron, P.; Eveland, S. S.; Raetz, C. R. H.; Hyland, S. A.; Anderson, M. S. The envA permeability/cell division gene of Escherichia coli encodes the second enzyme of lipid A biosynthesis. UDP-3- O -(R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase J. Biol. Chem. 1995, 270 (51) 30384-30391
9. Onishi, H. R.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M.-H.; Patchett, A. A.; Galloway, S. M.; Hyland, S. A. Antibacterial agents that inhibit lipid A biosynthesis Science 1996, 274 (5289) 980-982 (Pubitemid 26398419)
10. Barb, A. W.; Zhou, P. Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis Curr. Pharm. Biotechnol. 2008, 9 (1) 9-15 (Pubitemid 351266965)
11. Cuny, G. D., A new class of UDP-3- O -(R -3-hydroxymyristol)- N -acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections: PCT application WO 2008027466. Expert Opin. Ther. Pat. 2009, 19 (6), 893-899
12. Faruk Mansoor, U.; Vitharana, D.; Reddy, P. A.; Daubaras, D. L.; McNicholas, P.; Orth, P.; Black, T.; Arshad Siddiqui, M. Design and synthesis of potent Gram-negative specific LpxC inhibitors Bioorg. Med. Chem. Lett. 2011, 21 (4) 1155-1161
13. Liang, X.; Lee, C.-J.; Chen, X.; Chung, H. S.; Zeng, D.; Raetz, C. R. H.; Li, Y.; Zhou, P.; Toone, E. J. Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold Bioorg. Med. Chem. 2011, 19 (2) 852-860
14. Barb, A. W.; Leavy, T. M.; Robins, L. I.; Guan, Z.; Six, D. A.; Zhou, P.; Bertozzi, C. R.; Raetz, C. R. H. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC Biochemistry (Moscow) 2009, 48 (14) 3068-3077
15. Cole, K. E.; Gattis, S. G.; Angell, H. D.; Fierke, C. A.; Christianson, D. W. Structure of the Metal-Dependent Deacetylase LpxC from Yersinia enterocolitica Complexed with the Potent Inhibitor CHIR-090 Biochemistry (Moscow) 2011, 50 (2) 258-265
16. Whittington, D. A.; Rusche, K. M.; Shin, H.; Fierke, C. A.; Christianson, D. W. Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis Proc. Natl. Acad. Sci. U.S.A. 2003, 100 (14) 8146-8150 (Pubitemid 36842513)
17. Mochalkin, I.; Knafels, J. D.; Lightle, S. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor Protein Sci. 2008, 17 (3) 450-457 (Pubitemid 351281545)
18. a Analysis of an Active Site Histidine: Insights into the Mechanism and Inhibitor Design Biochemistry (Moscow) 2005, 44 (4) 1114-1126 (Pubitemid 40208991)
19. Anderson, G. M., III; Kollman, P. A.; Domelsmith, L. N.; Houk, K. N. Methoxy group nonplanarity in o -dimethoxybenzenes. Simple predictive models for conformations and rotational barriers in alkoxyaromatics J. Am. Chem. Soc. 1979, 101 (9) 2344-2352 (Pubitemid 9454676)
20. Kalgutkar, A. S.; Obach, R. S.; Maurer, T. S. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions Curr. Drug Metab. 2007, 8 (5) 407-447 (Pubitemid 47603408)
21. Lomovskaya, O.; Zgurskaya, H. I.; Totrov, M.; Watkins, W. J. Waltzing transporters and "the dance macabre" between humans and bacteria Nature Rev. Drug Discovery 2007, 6 (1) 56-65 (Pubitemid 46020286)
22. Chuanchuen, R.; Beinlich, K.; Hoang, T. T.; Becher, A.; Karkhoff-Schweizer, R. R.; Schweizer, H. P. Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-OprJ Antimicrob. Agents Chemother. 2001, 45 (2) 428-432 (Pubitemid 32105276)
23. Screen was performed by Cerep Corp. 15318 NE 95th St. Redmond, WA 98052, USA; www.cerep.com.
24. Dalvie, D.; Cosker, T.; Boyden, T.; Zhou, S.; Schroeder, C.; Potchoiba, M. J. Metabolism distribution and excretion of a matrix metalloproteinase-13 inhibitor, 4-[4-(4-fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4- carboxylic acid hydroxyamide (CP-544439), in rats and dogs: assessment of the metabolic profile of CP-544439 in plasma and urine of humans Drug Metab. Dispos. 2008, 36 (9) 1869-1883
25. Benet, L. Z.; Hoener, B.-A. Changes in plasma protein binding have little clinical relevance Clin. Pharmacol. Ther. 2002, 71 (3) 115-121 (Pubitemid 34271114)
26. Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nature Rev. Drug Discovery 2010, 9 (12) 929-939
27. Langsdorf, E. F.; Malikzay, A.; Lamarr, W. A.; Daubaras, D.; Kravec, C.; Zhang, R.; Hart, R.; Monsma, F.; Black, T.; Ozbal, C. C.; Miesel, L.; Lunn, C. A. Screening for antibacterial inhibitors of the UDP-3- O -(R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase (LpxC) using a high-throughput mass spectrometry assay J. Biomol. Screening 2010, 15 (1) 52-61