Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+Exchanger Type 3 (NHE3).
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 13d 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 13d 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 13d, 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.
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Nils
N
Rackelmann
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Hans
H
Matter
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Heinrich
H
Englert
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Markus
M
Follmann
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Thomas
T
Maier
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
John
J
Weston
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Petra
P
Arndt
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Winfried
W
Heyse
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Katharina
K
Mertsch
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Klaus
K
Wirth
Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
Laurent
L
Bialy
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D017207:Rats, Sprague-Dawley; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013552:Swine
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007189:Indans; C000613385:SLC9A3 protein, human; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C006545:2-aminoindan; D019389:Cytochrome P-450 CYP2D6