FimH Antagonists: Bioisosteres
To Improve the in Vitro
and in Vivo PK/PD Profile

Kleeb, Simon; Pang, Lijuan; Mayer, Katharina; Eris, Deniz; Sigl, Anja; Preston, Roland C.; Zihlmann, Pascal; Sharpe, Timothy; Jakob, Roman P.; Abgottspon, Daniela; Hutter, Aline S.; Scharenberg, Meike; Jiang, Xiaohua; Navarra, Giulio; Rabbani, Said; Smiesko, Martin; Lüdin, Nathalie; Bezençon, Jacqueline; Schwardt, Oliver; Maier, Timm; Ernst, Beat

doi:10.1021/jm501524q.s001

jm501524q_si_001.pdf (2.03 MB)

FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile

journal contribution

posted on 2015-03-12, 00:00 authored by Simon Kleeb, Lijuan Pang, Katharina Mayer, Deniz Eris, Anja Sigl, Roland C. Preston, Pascal Zihlmann, Timothy Sharpe, Roman P. Jakob, Daniela Abgottspon, Aline S. Hutter, Meike Scharenberg, Xiaohua Jiang, Giulio Navarra, Said Rabbani, Martin Smiesko, Nathalie Lüdin, Jacqueline Bezençon, Oliver Schwardt, Timm Maier, Beat Ernst

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.