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Exploration of pyrrole derivatives to ?nd an effective potassium- competitive acid blocker with moderately long-lasting suppression of gastric acid secretion Haruyuki Nishida ? , Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono, Kazuo Nakai, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Akio Imanishi, Hideo Fukui, Fumio Itoh Pharmaceutical Research Division: Takeda Pharmaceutical Company, Ltd.

, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan a r t i c l e i n f o Article history: Received

18 March

2017 Revised

24 April

2017 Accepted

26 April

2017 Available online

27 April

2017 Keywords: Potassium-competitive acid blocker Transfer behavior to the stomach Rapid onset Moderately long-lasting acid suppression a b s t r a c t With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could per- fectly 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 effec- tive drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, ?uoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, ?uorine atom at posi- tion 4, and a 4-Me-2-Py sulfonyl group at the ?rst position of the pyrrole ring, showed potent gastric acid- suppressive action and moderate duration of action in animal models. On the basis of structural proper- ties including a slightly larger ClogP value (1.95), larger logD 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 administra- tion. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. ?

2017 Elsevier Ltd. All rights reserved. 1. Introduction Gastric H+ ,K+ -ATPase is the key enzyme at the ?nal step of gas- tric acid secretion. Its inhibition is thought to be especially effec- tive for control of gastric acid secretion;

accordingly, the development of H+ ,K+ -ATPase inhibitors for the treatment of acid-related diseases has attracted considerable interest.1 Proton pump inhibitors (PPIs) such as lansoprazole, omepra- zole, rabeprazole, and pantoprazole inhibit gastric H+ ,K+ -ATPase by covalently binding to its sulfhydryl group, resulting in inhibition of gastric acid secretion.2C6 Although PPIs are now the mainstay of therapy for acid-related diseases, there are several limitations in terms of acid lability, delayed onset of action, variations of ef?cacy among patients (largely because of CYP2C19-mediated metabo- lism), and insuf?cient inhibition of nocturnal acid break- through.7C11 Potassium-competitive acid blockers (P-CABs), a new class of acid suppressors with a mode of action different from that of PPIs, are expected to offer some therapeutic bene?ts such as better symptom control and faster remission of gastroesophageal re?ux disease and of other acid-related diseases. P-CABs, as the name suggests, inhibit H+ ,K+ -ATPase activity in gastric parietal cells reversibly and in a potassium-competitive manner.12 In our previous paper,13 we have reported that compound 2a, as a novel P-CAB that has quite low lipophilicity and excellent ADME- Tox parameters, has a potent H+ ,K+ -ATPase inhibitory activity in vitro and potent and long-lasting inhibition of histamine-induced http://dx.doi.org/10.1016/j.bmc.2017.04.034 0968-0896/?