TY - JOUR
T1 - Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC)
T2 - Optimization through Iterative Rational Drug Design
AU - Maddirala, Amarendar Reddy
AU - Klein, Roger
AU - Pinkner, Jerome S.
AU - Kalas, Vasilios
AU - Hultgren, Scott J.
AU - Janetka, James W.
N1 - Funding Information:
We thank the National Institutes of Health (NIH) for funding awarded by the NIDDK, R01DK10884.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/1/24
Y1 - 2019/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85060526011&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01561
DO - 10.1021/acs.jmedchem.8b01561
M3 - Article
C2 - 30540910
AN - SCOPUS:85060526011
VL - 62
SP - 467
EP - 479
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 2
ER -