Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers

Publication date: Available online 6 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Toshihiro Imaeda, Koji Ono, Kazuo Nakai, Yasunobu Hori, Jun Matsukawa, Terufumi Takagi, Yasushi Fujioka, Naoki Tarui, Mitsuyo Kondo, Akio Imanishi, Nobuhiro Inatomi, Masahiro Kajino, Fumio Itoh, Haruyuki Nishida
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H⁺,K⁺-ATPase and can strongly bind to the K⁺-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H⁺,K⁺-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Graphical abstract

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