| Acid-related diseases (ARDs) are one class of gastrointestinal disorders closely related to the secretion of gastric acid, including gastroesophageal reflux disease (GERD), dyspepsia, gastritis, gastrointestinal ulcer, duodenitis, Zollinger-Ellison syndrome and non-steroidal anti-inflammatory drug-induced digestive diseases. Worldwide, ARDs’incidence showed an increasing trend. ARDs have become one of China’s major diseases, seriously affecting the quality of life of patients, and bringing huge economic burden to patients.Clinically, proton pump inhibitors (PPIs) are widely used in the treatment of ARDs, for the primary therapy of such diseases. Due to some limitations, PPIs for nighttime inhibition of gastric acid secretion is insufficient in some patients, nocturnal acid breakthrough is widespread, affecting the therapeutic effects. Thus a new research direction of acid-suppressing agents:potassium competitive acid blocker (P-CAB) is spawned. Different from traditional PPIs, P-CAB by competitive inhibition of proton pump (H+, K+-ATPase) in the function of K+is a reversible antagonist. Since the effect is independent of proton pump activation conditions, P-CABs can significantly reduce the occurrence of nocturnal acid breakthrough clinically.TAK-438(5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methanamine fumarate) was developed by Takeda Pharmaceuticals as a potassium competitive acid blocker (P-CAB). In vitro experiments showed that the bioactivity of this compound to inhibit the proton pump was400times nore than that of lansoprazole, with respect to Na+, K+-ATPase inhibition of more than500-fold selectivity. In the cultured rabbit gastric glands, TAK-438showed higher enrichment rate and slower clearance rate, which means it has a stronger and longer lasting efficacy in vivo. TAK-438entered phase Ⅲ clinical study in September2011, and is currently at the end of clinical studies. However, the poor-solubility in water greatly influences the parameters of its oral absorption kinetics, which limits the acid-suppressing effect of this compound. TAK-438has a tablet formulation only, and can not meet the clinical needs of some patients with ARDs when it is difficult for them to swallow tablets.In this study, we designed water-soluble organic salts with5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methanamine, the active compound of TAK-438. The salts can solve the problem of poor water-solubility, to improve the bioavailability, treat gastric acid related diseases with faster onset of action, and meet different clinical needs.In this study, four organic acid salts of TAK-438were synthesized through the corrected process route, including pyroglutamate, lactate, ethane sulfonate and malonate, and their structures were confirmed by mass spectrometry,’H-NMR and13C-NMR, X-ray powder diffraction, melting point, etc. Target compounds were tested in water solubility, and the order of water-solubility was pyroglutamate, lactate (highly soluble)> esylate, malonate (soluble)> TAK-438(fumarate, very slightly soluble). Pyroglutamate’s solubility in water was1000times more than fumarate, and greatly improved the solubility of TAK-438.In in vivo study with SD rats, onset of TAK-438pyroglutamate was faster than TAK-438, approximately1hour ahead; In oral absorption kinetics experiments using Wistar rats, TAK-438pyroglutamate greatly improved the absorption kinetic parameters, compared with TAK-438. TAK-438pyroglutamate has excellent water solubility and absorption kinetics, which benefits further studies of drug toxicology, bioavailability assay, etc. |
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