title: FimH antagonists: bioisosteres to improve the in vitro and in vivo PK/PD profile.
abstract: Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl α-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(α-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.
authors: Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors: Simon
authors: S
authors: Kleeb
authors: Lijuan
authors: L
authors: Pang
authors: Katharina
authors: K
authors: Mayer
authors: Deniz
authors: D
authors: Eris
authors: Anja
authors: A
authors: Sigl
authors: Roland C
authors: RC
authors: Preston
authors: Pascal
authors: P
authors: Zihlmann
authors: Timothy
authors: T
authors: Sharpe
authors: Roman P
authors: RP
authors: Jakob
authors: Daniela
authors: D
authors: Abgottspon
authors: Aline S
authors: AS
authors: Hutter
authors: Meike
authors: M
authors: Scharenberg
authors: Xiaohua
authors: X
authors: Jiang
authors: Giulio
authors: G
authors: Navarra
authors: Said
authors: S
authors: Rabbani
authors: Martin
authors: M
authors: Smiesko
authors: Nathalie
authors: N
authors: Lüdin
authors: Jacqueline
authors: J
authors: Bezençon
authors: Oliver
authors: O
authors: Schwardt
authors: Timm
authors: T
authors: Maier
authors: Beat
authors: B
authors: Ernst
mesh_terms: D018830:Adhesins, Escherichia coli; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008362:Mannosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000187:drug effects*
chemical_list: C000598568:3'-chloro-4'-(mannopyranosyloxy)biphenyl-4-carbonitrile; D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D001713:Biphenyl Compounds; D008362:Mannosides; C058769:fimH protein, E coli; D036781:Fimbriae Proteins