Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia.
Michihiro MaemotoYuuki HirataShintaro HosoeJun OuchiKazuya NarushimaEmi AkizawaYoshiro TsujiHidenori TakadaArata YanagisawaSatoshi ShutoPublished in: Journal of medicinal chemistry (2022)
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 (IC 50 = 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 (IC 50 = 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.
Keyphrases
- small molecule
- protein protein
- oxidative stress
- photodynamic therapy
- cell proliferation
- mass spectrometry
- signaling pathway
- transcription factor
- combination therapy
- liquid chromatography
- endoplasmic reticulum stress
- replacement therapy
- liquid chromatography tandem mass spectrometry
- gas chromatography mass spectrometry
- tandem mass spectrometry
- cell cycle arrest