Journal of Medicinal Chemistry p. 8812 - 8829 (2016)
Update date:2022-08-15
Topics:
Rackelmann, Nils
Matter, Hans
Englert, Heinrich
Follmann, Markus
Maier, Thomas
Weston, John
Arndt, Petra
Heyse, Winfried
Mertsch, Katharina
Wirth, Klaus
Bialy, Laurent
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.
View MoreShanghai Forever Synthesis Co.,Ltd.
Contact:021-61124658
Address:Zhoukang Road,Pudong New District,Shanghai,China
Contact:+86-15995924277
Address:WuZhongOu suzhou new south road 89
NINGBO PANGS CHEM INT’L CO.,LTD.
Contact:+86-574-27666845
Address:FLOOR 21,BUILDING NO.11,XIN TIAN DI,NO.689 SHI JI ROAD,NINGBO CHINA
Contact:17316303296
Address:240 Amboy Ave
Changzhou Kingyo Chemical Corporation Ltd.
website:http://www.kingyochem.com
Contact:+86-519-85105717
Address:19# Wuqing North Road, Changzhou , Jiangsu, China
Doi:10.1021/jo100173f
(2010)Doi:10.1246/cl.2012.940
(2012)Doi:10.1039/b917410a
(2010)Doi:10.1007/s11746-012-2177-9
(2013)Doi:10.1021/om00111a019
(1989)Doi:10.1021/ja01234a020
(1944)