Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.
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.
Palmer
Andreas M
AM
NYCOMED GmbH, Departments of Medicinal Chemistry, Biochemistry, Pharmacology, and Physicochemistry, Byk-Gulden-Strasse 2, D-78467 Konstanz, Germany. andreas.palmer@nycomed.com
Chiesa
Vittoria
V
Schmid
Anja
A
Münch
Gabriela
G
Grobbel
Burkhard
B
Zimmermann
Peter J
PJ
Brehm
Christof
C
Buhr
Wilm
W
Simon
Wolfgang-Alexander
WA
Kromer
Wolfgang
W
Postius
Stefan
S
Volz
Jürgen
J
Hess
Dietmar
D
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
D000143:Acids; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D011188:Potassium