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J Med Chem. 2019 Jan 24;62(2):467-479. doi: 10.1021/acs.jmedchem.8b01561. Epub 2019 Jan 2.

Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design.

Author information

1
Department of Biochemistry and Molecular Biophysics , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.
2
Department of Molecular Microbiology , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.
3
Center for Women's Infectious Disease Research, Department of Molecular Microbiology , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.

Abstract

The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 by replacing the carboxylate with a sulfonamide as in 50. Other groups which can accept H-bonds were also tolerated. We pursued further modifications to the biphenyl aglycone resulting in significantly improved activity. Two of the most potent compounds, 86 (IC50 = 0.051 μM) and 90 (IC50 = 0.034 μM), exhibited excellent metabolic stability in mouse plasma and liver microsomes but showed only limited oral bioavailability (<1%) in rats. Compound 84 also showed a good pharmacokinetic (PK) profile in mice after IP dosing with compound exposure above the IC50 for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs.

PMID:
30540910
PMCID:
PMC6467771
[Available on 2020-01-24]
DOI:
10.1021/acs.jmedchem.8b01561

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