Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion
| Autor: | Hideo Fukui, Ikuo Fujimori, Nobuhiro Inatomi, Koji Ono, Keizo Hirase, Haruyuki Nishida, Akio Imanishi, Yasuyoshi Arikawa, Fumio Itoh, Yasunobu Hori, Jun Matsukawa, Kazuo Nakai, Yasushi Fujioka |
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| Rok vydání: | 2017 |
| Předmět: |
Drug
Male Stereochemistry Potassium media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science chemistry.chemical_element Administration Oral Ring (chemistry) 01 natural sciences Biochemistry Gastric Acid Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound H(+)-K(+)-Exchanging ATPase Structure-Activity Relationship 0302 clinical medicine Drug Discovery Animals Humans Pyrroles Molecular Biology Pyrrole media_common Sulfonyl chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Proton Pump Inhibitors Combinatorial chemistry 0104 chemical sciences Rats chemistry Molecular Medicine Gastric acid 030211 gastroenterology & hepatology Lead compound Derivative (chemistry) |
| Zdroj: | Bioorganicmedicinal chemistry. 25(13) |
| ISSN: | 1464-3391 |
| Popis: | With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j , which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger C log P value (1.95), larger log D value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a , compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. |
| Databáze: | OpenAIRE |
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