title: 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.
authors.affiliation: NYCOMED GmbH, Departments of Medicinal Chemistry, Biochemistry, Pharmacology, and Physicochemistry, Byk-Gulden-Strasse 2, D-78467 Konstanz, Germany. andreas.palmer@nycomed.com
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Palmer
authors.forename: Vittoria
authors.initials: V
authors.lastname: Chiesa
authors.forename: Anja
authors.initials: A
authors.lastname: Schmid
authors.forename: Gabriela
authors.initials: G
authors.lastname: Münch
authors.forename: Burkhard
authors.initials: B
authors.lastname: Grobbel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Zimmermann
authors.forename: Christof
authors.initials: C
authors.lastname: Brehm
authors.forename: Wilm
authors.initials: W
authors.lastname: Buhr
authors.forename: Wolfgang-Alexander
authors.initials: WA
authors.lastname: Simon
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kromer
authors.forename: Stefan
authors.initials: S
authors.lastname: Postius
authors.forename: Jürgen
authors.initials: J
authors.lastname: Volz
authors.forename: Dietmar
authors.initials: D
authors.lastname: Hess
mesh_terms: D000143:Acids / Q000037:antagonists & inhibitors*; D000818:Animals; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D000143:Acids; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D011188:Potassium