RT Journal Article
SR Electronic
T1 Soraprazan: Setting New Standards in Inhibition of Gastric Acid Secretion
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 866
OP 874
DO 10.1124/jpet.107.120428
VO 321
IS 3
A1 Simon, W. A.
A1 Herrmann, M.
A1 Klein, T.
A1 Shin, J. M.
A1 Huber, R.
A1 Senn-Bilfinger, J.
A1 Postius, S.
YR 2007
UL http://jpet.aspetjournals.org/content/321/3/866.abstract
AB After treatment of millions of patients suffering from gastroesophageal reflux disease (GERD) and other acid-related ailments with proton pump inhibitors, there are still unmet medical needs such as rapid and reliable pain relief, especially for nocturnal acid breakthrough. In this work, we introduce and characterize the biochemistry and pharmacology of the potassium-competitive acid blocker (P-CAB) soraprazan, a novel, reversible, and fast-acting inhibitor of gastric H,K-ATPase. Inhibitory and binding properties of soraprazan were analyzed together with its mode of action, its selectivity, and its in vivo potency. This P-CAB has an IC50 of 0.1 μM if measured with ion leaky vesicles and of 0.19 μM in isolated gastric glands. With a Ki of 6.4 nM, a Kd of 26.4 nM, and a Bmax of 2.89 nmol/mg, this compound is a highly potent and reversible inhibitor of the H,K-ATPase. Soraprazan shows immediate inhibition of acid secretion in various in vitro models and in vivo and was found to be more than 2000-fold selective for H,K-ATPase over Na,K- and Ca-ATPases. Soraprazan is superior to esomeprazole in terms of onset of action and the extent and duration of pH elevation in vivo in the dog. Rapid and consistent inhibition of acid secretion by soraprazan renders the P-CABs a promising group of compounds for therapy of GERD. The American Society for Pharmacology and Experimental Therapeutics