Pharmacological Profile of Novel Acid Pump Antagonist 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methyl cyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526)

The gastric H,K-ATPase, a member of the P 2 -type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven Nlinked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E 1 (ion site in) to an E 2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E 2 P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E 2 P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E 1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

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“…Another structure of APA is CS-526. CS-526 has the pyrrolopyridazine structure and is also under development [20].…”

Section: Acid Pump Antagonistsmentioning

confidence: 99%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

220

181

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“…It was reported that the duration of the inhibitory effect of CS-526 and SCH28080, the aforementioned P-CABs, on gastric acid secretion was shorter than that of PPIs in rats and dogs (Long et al, 1983;Ito et al, 2007), and the effect of TAK-438 was more potent and had a longer duration than that of SCH28080 in rats (Hori et al, 2010). These findings clearly indicate that TAK-438 is a novel P-CAB that exerts a stronger and longer-lasting inhibitory effect on gastric acid secretion than PPIs and the aforementioned P-CABs.…”

Section: Characteristics Of Antisecretory Effect Of Tak-438 801mentioning

confidence: 99%

“…This mechanism allows rapid inhibition of the pump without the need for acidity at its luminal surface because the pump is blocked in midcycle. Several structural derivatives, e.g., imidazopyridines such as SCH28080 (Wallmark et al, 1987) and 8-[(2,6-dimethylbenzyl)amino]-N-[2-hydroxyethyl]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxyamide (AZD0865) (Gedda et al, 2007), pyrimidines (Yu et al, 2004), imidazonaphthyridines (Simon et al, 2007), and pyrrolopyridazines such as 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo [2,3-d]pyridazine (CS-526) (Ito et al, 2007), have been evaluated as P-CABs. These compounds have higher pK a values than PPIs and are stable at a low pH.…”

Section: Introductionmentioning

confidence: 99%

A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals

Hori¹,

Matsukawa²,

Takeuchi³

et al. 2011

J Pharmacol Exp Ther

137

108

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Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-Nmethylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI, to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

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“…We have shown the potent and reversible inhibitory properties of CS-526 against porcine H ϩ ,K ϩ -ATPase without a covalent binding formation. The potent gastric acid inhibitory effects and antiulcer efficacies of CS-526 have also been shown, and the efficacies of CS-526 are comparable with those of PPIs such as omeprazole, lansoprazole, and rabeprazole (Ito et al, 2007).…”

mentioning

confidence: 85%

“…The major classes of APAs are imidazopyridine (Wallmark et al, 1987;Kromer et al, 2000;Gedda et al, 2007) and acyl quinoline derivatives (Keeling et al, 1991;Pope et al, 1995;Cheon et al, 2001), and most of these compounds have been shown to inhibit H ϩ ,K ϩ -ATPase in a K ϩ -competitive mechanism without any covalent binding, thereby initiating reversible inhibition of H ϩ ,K ϩ -ATPase activities. CS-526 is a novel acid suppressant that is different from PPIs and the aforementioned APAs in that its chemical structure includes a pyrrolopyridazine structure (Ito et al, 2007). We have shown the potent and reversible inhibitory properties of CS-526 against porcine H ϩ ,K ϩ -ATPase without a covalent binding formation.…”

mentioning

confidence: 91%