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

Abstract

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.

Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

“…During the 10-year period, a number of noncardiovascular drugs that block human ether-a-go-go related gene (hERG) K + channels and delay cardiac repolarization have been withdrawn because of sudden cardiac deaths associated with drug-induced acquired length of time between the start of the Q wave and end of the T wave on an electrocardiogram (QT) interval prolongation. , To reduce risks of drugs as early as possible during development, QT prolongation risks are predicted through the in vitro hERG channel inhibition activity (IC 50 ) in mammalian cell lines . Thus, the most potent compounds 27aa and 58 were selected to evaluate their hERG K + channel inhibition using Qpatch 16X assay. − As shown in Table , all tested compounds showed mild inhibitory effects on the hERG channel compared with the control drugs.…”

Review article: potassium‐competitive acid blockers for the treatment of acid‐related disorders

“…For over a decade, multiple studies have covered the development of the P‐CABs and evaluation of their safety and efficacy in acid‐related disorders 14‐16 . Some of the original agents in this class such as SCH28080, SK&F96067 (BY067), SK&F97574 (BY574), BY841 and AZD0865 are no longer in development (Table 2).…”

(2S*,3S*,3aS*,6S*,7aR*)-3-Hydroxy-2-[(2R*,3S*)-3-isopropyloxiran-2-yl]-3,6-dimethyl-3,3a,5,6,7,7a-hexahydro-1-benzofuran-4(2H)-one

“…The title compound was synthesized as a potential gastric cytoprotective agent. For background to gastric diseases, see: Palmer et al (2010). For pharmacological uses of bisabolangelone, a sesquiterpene isolated from the roots of Angelica polymorpha Maxim, see: Fang & Liao (2006); Muckensturm et al (1981).…”