Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia

In the face of escalating metabolic disease prevalence,
largely
driven by modern lifestyle factors, this study addresses the critical
need for novel therapeutic approaches. We have identified the sodium-coupled
citrate transporter (NaCT or SLC13A5) as a target for intervention.
Utilizing rational drug design, we developed a new class of SLC13A5
inhibitors, anchored by the hydroxysuccinic acid scaffold, refining
the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with
an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3’s efficacy in reducing triglyceride levels in
OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior
pharmacokinetic properties and effectively lowered triglyceride and
total cholesterol levels in diverse mouse models (PCN-stimulated and
starvation-induced), without detectable toxicity. These findings not
only spotlight LBA-3 as a promising candidate for hyperlipidemia
treatment but also exemplify the potential of targeted molecular design
in advancing metabolic disorder therapeutics.