New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as multidrug resistance inhibitors
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The specific aim of this study was to evaluate a series of new dihydropyridine (DHP) and pyridine compounds as multidrug resistance (MDR) inhibitors in cancer chemotherapy. Thirty compounds have been synthesized based on structure optimizations of niguldipine seeking to have a greater inhibitory effect on P-glycoprotein (P-gp, MDR1) and negligible Ca 2+ channel binding. Effects of these newly synthesized compounds on three MDR transporters P-gp, multidrug resistance protein 1 (MRP1) and breast cancer resistant protein (BCRP) were investigated in human breast cancer MCF-7/adr cells (Pgp-overexpressing), human small cell lung cancer H69AR cells (MRP1-overexpressing) and human non-small cell lung cancer H460/MX20 cells (BCRP overexpressing). Drug accumulation and cytotoxicity studies were conducted in these cell lines. Ca 2+ channel binding activities were evaluated using rat brain cortex membranes. Quantitative structure-activity and quantitative-pharmacokinetics relationships (QSAR/QSPKR) were analyzed by 3D molecular modeling to identify new molecules with potent MDR inhibition, reduced Ca 2+ antagonistic activity and predicted favorable pharmacokinetic characteristics. Twenty-seven out of 30 new compounds exhibited inhibition of P-gp activity; moderate MRP1 modulatory effect was observed in several new compounds; 24 out of 25 compounds inhibited BCRP. Potent inhibition of both P-gp and BCRP were observed. Cytotoxicity studies with doxorubicin and mitoxantrone confirmed our accumulation study results. Ca 2+ channel binding activity was low for 8 compounds, and negligible for all others. Three-dimensional QSAR and QSPKR models were developed and, based on the models, one DHP compound (named DHP-014) was selected for further in vivo pharmacokinetics studies in Sprague-Dawley rats. The pharmacokinetics of DHP-014 was evaluated after the intravenous and oral administration of multiple doses. Pharmacokinetic modeling indicated a non-linear elimination process at higher doses and low bioavailability (F ∼ 8%). A pilot study examining concomitant DHP-014 administration (20 mg/kg) with topotecan was conducted in Sprague-Dawley rats. A 2-fold increase of the systemic exposure and a significant increased in the maximal plasma concentration of topotecan, a BCRP and P-gp substrate, was observed in rats when oral topotecan 2 mg/kg was combined with 20 mg/kg DHP-014, indicating significant in vivo inhibition. Our investigations have characterized the effects of newly synthesized DHP/pyridine compounds on P-gp-, MRP1- and BCRP-mediated efflux and chemotherapeutic agent cytotoxicity. We have identified compounds that have potential as clinically applicable MDR modulators.