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  3. Design, synthesis and biological evaluation of novel indole derivatives as gut-selective NaPi2b inhibitors

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

  • Bioorg Med Chem. 2022 Jul 15;66:116783. doi: 10.1016/j.bmc.2022.116783.
Yasunobu Ushiki 1,  Kenichi Kawabe 2,  Kumiko Yamamoto-Okada 2,  Fumito Uneuchi 2,  Yuta Asanuma 2,  Chitose Yamaguchi 2,  Hiroshi Ohta 2,  Tsuyoshi Shibata 2,  Tomohiro Abe 2,  Lisa Okumura-Kitajima 2,  Yuki Kosai 2,  Mayumi Endo 2,  Katsumasa Otake 2,  Eiji Munetomo 2,  Teisuke Takahashi 2,  Hiroyuki Kakinuma 2
Affiliations

Affiliations

  • 1 Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: y-ushiki@taisho.co.jp.
  • 2 Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
PMID: 35576656 DOI: 10.1016/j.bmc.2022.116783
Abstract

Intestinal sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors are expected to be potential new candidates for anti-hyperphosphatemia drugs. However, a risk of on-target side effects based on the inhibition of NaPi2b in the lung and testis has been reported.In this article, we report on our identification of novel indole derivatives as gut-selective NaPi2b inhibitors with good activity, low systemic exposure and moderate hydrophobicity.In particular, gut-selective compound 27, with even lower bioavailability and lower systemic exposure as compared to previously reported pyridine derivatives, demonstrated excellent phosphate absorption-inhibitory effect in SD rats. Compound 27 has an ideal profile and appears to offer promise as a candidate drug for the treatment of hyperphosphatemia, with minimal risk of side effects due to systemic exposure.

Keywords

Bioavailability; Gut-selective; Hyperphosphatemia; NaPi2b; NaPi2b inhibitor.

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