Soraprazan: setting new standards in inhibition of gastric acid secretion.
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 IC(50) of 0.1 microM if measured with ion leaky vesicles and of 0.19 microM in isolated gastric glands. With a K(i) of 6.4 nM, a K(d) of 26.4 nM, and a B(max) 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.
Simon
W A
WA
Department of Biochemistry Gastroenterology, ALTANA Pharma AG, Byk-Gulden Strasse 2, 78467 Konstanz, Germany.
Herrmann
M
M
Klein
T
T
Shin
J M
JM
Huber
R
R
Senn-Bilfinger
J
J
Postius
S
S
D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D064098:Esomeprazole / Q000737:chemistry / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives; D009550:Nigericin / Q000737:chemistry / Q000494:pharmacology; D011188:Potassium / Q000737:chemistry / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis / Q000235:genetics; D013270:Stomach / Q000187:drug effects / Q000201:enzymology; D013552:Swine
C503551:ATP1B1 protein, human; D000897:Anti-Ulcer Agents; D001552:Benzazepines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009287:Naphthyridines; D054328:Proton Pump Inhibitors; C035235:Sch 28080; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide; C521310:soraprazan; C499076:ATP1A1 protein, human; D017506:H(+)-K(+)-Exchanging ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D064098:Esomeprazole; D009550:Nigericin; D011188:Potassium