Tetrahydrochromenoimidazoles as Potassium-Competitive Acid Blockers (P-CABs): Structure-Activity Relationship of Their Antisecretory Properties and Their Affinity toward the hERG Channel

被引：18

作者：

Palmer, Andreas M. ^{[1
,2
,3
,4
]}

Chiesa, Vittoria ^{[1
,2
,3
,4
]}

Schmid, Anja ^{[1
,2
,3
,4
]}

Muench, Gabriela ^{[1
,2
,3
,4
]}

Grobbel, Burkhard ^{[1
,2
,3
,4
]}

Zimmermann, Peter J. ^{[1
,2
,3
,4
]}

Brehm, Christof ^{[1
,2
,3
,4
]}

Buhr, Wilm ^{[1
,2
,3
,4
]}

Simon, Wolfgang-Alexander ^{[1
,2
,3
,4
]}

Kromer, Wolfgang ^{[1
,2
,3
,4
]}

Postius, Stefan ^{[1
,2
,3
,4
]}

Volz, Juergen ^{[1
,2
,3
,4
]}

Hes, Dietmar ^{[5
]}

机构：

[1] NYCOMED GmbH, Dept Med Chem, D-78467 Constance, Germany

[2] NYCOMED GmbH, Dept Biochem, D-78467 Constance, Germany

[3] NYCOMED GmbH, Dept Pharmacol, D-78467 Constance, Germany

[4] NYCOMED GmbH, Dept Physicochem, D-78467 Constance, Germany

[5] NMI TT GmbH, D-72770 Reutlingen, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 09期

关键词：

ASYMMETRIC KETONE HYDROGENATION; POTENT REVERSIBLE INHIBITORS; GASTRIC H+/K+-ATPASE; TRICYCLIC IMIDAZOPYRIDINES; SECRETION; CATALYSTS; DISEASE;

D O I：

10.1021/jm100040c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established. In addition, efficacy and duration of the antisecretory action was examined for the most promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4.

引用

页码：3645 / 3674

页数：30

共 38 条

[1] Ligand structural aspects of hERG channel blockade [J].