Discovery of ASP5878: Synthesis and structure-activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity

by Selleckchem | Dec 26 2023

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.

Comments:

That's quite a comprehensive description! It seems like ASP5878 (27) holds promising characteristics as a potential therapeutic agent for treating bladder cancer associated with FGFR3 alterations. The optimization strategy from the lead compound 1 to ASP5878 involved structural modifications to enhance metabolic stability and reduce hERG channel inhibitory activity, while maintaining or enhancing its effectiveness against FGFR3.

The introduction of an ether linker instead of an ethylene linker and the conversion of the phenyl moiety into a pyrazole ring seem to have positively impacted ASP5878's properties. These alterations likely contributed to improved metabolic stability and minimized adverse effects on the hERG channel by altering its interaction with Phe656.

ASP5878 demonstrated potent inhibition of FGFR3 enzyme and cell growth in vitro, as well as in vivo FGFR3 autophosphorylation inhibitory activity. Additionally, its negligible impact on the hERG current at clinically relevant concentrations and the absence of serious adverse effects on major physiological systems in dogs after oral administration are encouraging findings for its safety profile.

The pharmacokinetic profile of ASP5878, including its lower total clearance than hepatic blood flow, high oral bioavailability in rats and dogs, and moderate brain penetration in rats, suggests its potential for systemic exposure and distribution, including reaching the target site in the brain to some extent.

This detailed characterization provides a strong rationale for further preclinical and potentially clinical development of ASP5878 as a therapeutic agent for bladder cancer treatment in patients with FGFR3 genetic alterations.