Design, synthesis and biological evaluation of novel pyridine derivatives as gut-selective NaPi2b inhibitors. (1st June 2022)

• Record Type: Journal Article
• Authors: Ushiki, Yasunobu; Kawabe, Kenichi; Yamamoto-Okada, Kumiko; Uneuchi, Fumito; Asanuma, Yuta; Yamaguchi, Chitose; Ohta, Hiroshi; Shibata, Tsuyoshi; Abe, Tomohiro; Okumura-Kitajima, Lisa; Kosai, Yuki; Endo, Mayumi; Otake, Katsumasa; Munetomo, Eiji; Takahashi, Teisuke; Kakinuma, Hiroyuki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 65(2022)
• Publication Date: 2022-06-01
• Subjects: Hyperphosphatemia -- NaPi2b -- NaPi2b inhibitor -- Gut-selective -- Bioavailability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128700
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We previously reported thiophene derivatives as gut-selective (minimally systemic) and potent sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors. However, these derivatives did not suppress phosphate absorption form the intestinal tract in Sprague-Dawley (SD) rats. The lack of efficacy in vivo could be due to the high hydrophobicity of these compounds. In this report, we identified novel pyridine derivatives as gut-selective NaPi2b inhibitors with good activity in vitro and relatively low hydrophobicity. Especially, gut-selective compound 20b suppressed phosphate absorption in SD rats. These results suggest that physical properties, such as the hydrophobicity of the compounds, might affect the in vivo efficacy.