Development of potent non-acylhydrazone inhibitors of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b)

Abstract

Inhibition of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b), responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Previously, we aimed to identify new drugs for hyperphosphatemia treatment and obtained zwitterionic compound 3 (IC50 = 64 nM) as a potent selective inhibitor of intestinal NaPi2b. This small-molecule compound is gut-restricted owing to its almost membrane-impermeable property. However, when compound 3, containing an acylhydrazone structure, is exposed to plasma, it is easily metabolized and likely produces an acetylhydrazine compound. Clinical studies have shown that acetylhydrazine is a risk factor for hepatic toxicity owing to its microsomal metabolism, wherein toxic reactive intermediates are formed.Therefore, in this study, we aimed to obtain potent NaPi2b inhibitors without an acylhydrazone structure to reduce the risk of hepatic toxicity. We developed compound 18, an anilide compound with zwitterionic property having potent phosphate uptake inhibitory activity in vitro (IC50 = 14 nM) and low bioavailability (FaFg = 5.9%). Oral administration of compound 18 in rats showed a reduction in phosphate absorption comparable to that observed with lanthanum carbonate, a clinically effective phosphate binder used in hyperphosphatemia treatment. Moreover, combined administration of compound 18 and lanthanum carbonate resulted in an additive effect on phosphate absorption inhibition in rats. Our findings suggest that combination therapy with lanthanum carbonate and compound 18 will not only provide better treatment outcomes for hyperphosphatemia but also reduce gastrointestinal side effects in patients.