2 research outputs found
Discovery and Optimization of 1‑Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na<sup>+</sup>/H<sup>+</sup> Exchanger Type 3 (NHE3)
The design, synthesis, and structure–activity
relationship
of 1-phenoxy-2-aminoindanes as inhibitors of the Na<sup>+</sup>/H<sup>+</sup> 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
Discovery and Optimization of 1‑Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na<sup>+</sup>/H<sup>+</sup> Exchanger Type 3 (NHE3)
The design, synthesis, and structure–activity
relationship
of 1-phenoxy-2-aminoindanes as inhibitors of the Na<sup>+</sup>/H<sup>+</sup> 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