Discovery and Optimization of 1‑Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na⁺/H⁺ Exchanger Type 3 (NHE3)

Abstract

The design, synthesis, and structure–activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na⁺/H⁺ exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with <b>13d</b> as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of <b>13d</b> then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally <b>13d</b>, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas