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
  • 1. Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: [email protected].
  • 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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