Design, synthesis and biological evaluation of novel indole derivatives as gut-selective NaPi2b inhibitors.
Ushiki Y, Kawabe K, Yamamoto-Okada K, Uneuchi F, Asanuma Y, Yamaguchi C, Ohta H, Shibata T, Abe T, Okumura-Kitajima L, Kosai Y, Endo M, Otake K, Munetomo E, Takahashi T, Kakinuma H.
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.