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.

The Tyrosine Gate of the Bacterial Lectin FimH: A Conformational Analysis by NMR Spectroscopy and X‐ray Crystallography

“…[15] An impressive example of this is represented by biphenyl mannoside 4,w ith an ortho-chloro substituent on the inner aromatic ring and ac yano group in the para position of the outer ring as ab ioorthogonal replacement fort he carboxylate group present in antagonist 3. [21] Both ring substituents of 4 reduce the electron density in the aglycone and therebye nhancet he p-p interaction, thus leadingt oam ore than tenfolda ffinity improvement relative to the unsubstituted antagonist 2 (Table 2, below). Besides the biphenyls 2 to 4,t hree other compound classes with multiple aromatic rings in nonplanar arrangements have been tested: 5 features a5 -nitroindolinyl moiety N-linked to an inner phenyl ring, [17] 6 extends an orthochlorophenyl system with squaric acida nd N-methyl-piperazine, [14b] and in 7 (for synthesis see the Supporting Information) an amide bond is inserted between two phenylr ings with ortho-chlorine and para-carboxylate substituents.…”

“…[15d, 21,26] The enthalpy term DH8 obs = À42.9 kJ mol À1 of 1,5-anhydromannitol (10)i ncludes the binding energies from van der Waals contacts and ten specific hydrogen bonds with the protein.…”

“…[20] As pecial focus is placed on the PK/PD (pharmacokinetic/pharmacodynamic) properties for oral bioavailability. [21] The ideal FimH antagonist for UTI treatment needs to be balanced between ar easonable solubility for effective dosage and ac ertaind egree of lipophilicity for efficient membrane permeation during oral absorption. Despite the availability of structurali nformation,r ational design of FimH antagonists has not alwaysl ed to the expected improvement in binding affinities.…”

Glycoconjugates and Glycomimetics as Microbial Anti-Adhesives

“…This is typically pursued with monovalent aryl mannosides [13][14][15][16][17] targeted to the FimH binding site by their mannose component and carrying extended aromatic aglycones that establish high affinity interaction with the tyrosine gate (3-5, Figure 1a). Extensive medicinal chemistry programs are under way, including the use of prodrugs and bioisosters to achieve optimal pharmacological profile of these structures [18]. These studies recapitulate the challenges faced by development of "traditional" drugs starting from carbohydrates structures, with specific problems and difficulties that are not encountered in other medicinal chemistry areas.…”

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

“…Continued improvement of this potent compound and others has focused on improving their pharmacokinetic behavior through a number of approaches, including the use of bioisosteres, as well as the development of prodrugs (186,187). The culmination of this work has led to the development of small, orally bioavailable compounds capable of preventing acute UTIs and treating chronic UTIs (188).…”