Design, synthesis and biological evaluation of novel pyridine derivatives as gut-selective NaPi2b inhibitors

Autor:	Yasunobu Ushiki, Kenichi Kawabe, Kumiko Yamamoto-Okada, Fumito Uneuchi, Yuta Asanuma, Chitose Yamaguchi, Hiroshi Ohta, Tsuyoshi Shibata, Tomohiro Abe, Lisa Okumura-Kitajima, Yuki Kosai, Mayumi Endo, Katsumasa Otake, Eiji Munetomo, Teisuke Takahashi, Hiroyuki Kakinuma
Rok vydání:	2022
Předmět:	Rats Sprague-Dawley Pyridines Organic Chemistry Clinical Biochemistry Drug Discovery Animals Pharmaceutical Science Molecular Medicine Thiophenes Molecular Biology Biochemistry Phosphates Rats
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 65:128700
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::042ae16f3d6bd5911bf0834ec8fa3dd9 https://doi.org/10.1016/j.bmcl.2022.128700 Zobrazit plný text záznamu Full Text from ScienceDirect