Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Abstract

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

“…Interestingly, heterozygotes may have some benefit relating to reduced liver citrate transport. A current focus in diabetes drug development targets the liver NaCT with small molecule inhibitors that do not penetrate the CNS (11,12). There is some evidence from other members of the SLC13 family that dimer formation can alter function, both homodimers (19) and heterodimers with other proteins (42).…”

“…In addition, we prepared the DelG mutant of hNaCT, with a nucleotide deletion of hepatocytes, NaCT expression is correlated with lipid accumulation and triglyceride synthesis (10,11). Furthermore, inhibition of NaCT-mediated citrate transport by the liver is emerging as a therapeutic approach for the treatment of metabolic disorders, such as diabetes (11,12). Treatment of animals with small molecule NaCT inhibitors (that do not enter the central nervous system (CNS)) increased citrate excretion in urine, decreased hepatic lipid production and reduced plasma glucose (11).…”

Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake

“…The syntheses of diacids PF-06649298 and PF-06649297 and monoacid PF-06757303 were previously reported (Huard et al, 2015). The syntheses of PF-06794266, PF-06793742, and PF-06761281 were also reported (Huard et al, 2016). PF-06761281 was commercially available via Sigma-Aldrich (cat.…”

“…PZ0318). The syntheses of PF-06746350 and PF-06741415 were similar to the methods described previously (Huard et al, 2016). Other reagents were obtained from Sigma-Aldrich unless specified.…”

“…Inhibition of hepatic extracellular citrate uptake through SLC13A5 has been suggested as a potential therapeutic approach to treat metabolic diseases (Huard et al, 2015(Huard et al, , 2016Li et al, 2016). The SLC13A family contains five family members: SLC13A1 and SLC13A4 mainly transport sulfate, and SLC13A2, SLC13A3, and SLC13A5 transport di-and tri-carboxylates such as citrate (Lee et al, 2005;Bergeron et al, 2013).…”