Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia

NaPi2b
is primarily expressed in the small intestine, lungs, and
testes and plays an important role in phosphate homeostasis. The inhibition
of NaPi2b, responsible for intestinal phosphate absorption, is considered
to reduce serum phosphate levels, making it a promising therapeutic
approach for hyperphosphatemia. Using a novel phosphate uptake inhibitor 3 (IC50 = 87 nM), identified from an in-house compound
collection in human NaPi2b-transfected cells as a prototype compound,
we conducted its derivatization based on a Ro5-deviated strategy to
develop orally administrable small-molecule NaPi2b inhibitors with
nonsystemic exposure. Consequently, compound 15, a zwitterionic
compound with a potent in vitro phosphate uptake inhibitory activity
(IC50 = 64 nM) and a low membrane permeability (Pe <
0.025 × 10–6 cm/s), was developed. Compound 15 showed a low bioavailability (F = 0.1%)
in rats and a reduction in phosphate absorption in the rat intestinal
loop assay comparable to sevelamer hydrochloride, a clinically effective
phosphate binder for treating hyperphosphatemia.