Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides

Zhenfu Han; Jerome S Pinkner; Bradley Ford; Erik Chorell; Jan M Crowley; Corinne K Cusumano; Scott Campbell; Jeffrey P Henderson; Scott J Hultgren; James W Janetka

doi:10.1021/jm300165m

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Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides

Journal article

Peer reviewed

Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides

Zhenfu Han, Jerome S Pinkner, Bradley Ford, Erik Chorell, Jan M Crowley, Corinne K Cusumano, Scott Campbell, Jeffrey P Henderson, Scott J Hultgren and James W Janetka

Journal of medicinal chemistry, Vol.55(8), pp.3945-3959

04/26/2012

DOI: 10.1021/jm300165m

PMCID: PMC3375398

PMID: 22449031

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Abstract

Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections.

Biofilms - drug effects

Biphenyl Compounds - pharmacokinetics

Adhesins, Escherichia coli

Mannosides - pharmacokinetics

Structure-Activity Relationship

Mannosides - chemistry

Fimbriae Proteins - antagonists & inhibitors

Hemagglutination Inhibition Tests

Animals

Urinary Tract Infections

Biphenyl Compounds - pharmacology

Biphenyl Compounds - chemical synthesis

Mannosides - pharmacology

Mannosides - chemical synthesis

Mice

Bacterial Adhesion - drug effects

Details

Title: Subtitle: Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides
Creators: Zhenfu Han - Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, Missouri 63110, USA
Jerome S Pinkner
Bradley Ford
Erik Chorell
Jan M Crowley
Corinne K Cusumano
Scott Campbell
Jeffrey P Henderson
Scott J Hultgren
James W Janetka
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.55(8), pp.3945-3959
DOI: 10.1021/jm300165m
PMID: 22449031
PMCID: PMC3375398
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Publisher: United States
Grant note: RC1 DK086378-01 / NIDDK NIH HHS RC1 DK086378 / NIDDK NIH HHS RC1 DK086378-02 / NIDDK NIH HHS 1RC1DK086378 / NIDDK NIH HHS
Language: English
Date published: 04/26/2012
Academic Unit: Pathology
Record Identifier: 9984047727902771

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