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

Amarendar Reddy Maddirala, Roger Klein, Jerome S. Pinkner, Vasilios Kalas, Scott J. Hultgren, James W. Janetka

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 (IC 50 = 0.051 μM) and 90 (IC 50 = 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 IC 50 for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs.

Original languageEnglish
Pages (from-to)467-479
Number of pages13
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
DOIs
StatePublished - Jan 24 2019

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