Bioorganic and Medicinal Chemistry p. 3447 - 3460 (2017)
Update date:2022-08-03
Topics:
Nishida, Haruyuki
Fujimori, Ikuo
Arikawa, Yasuyoshi
Hirase, Keizo
Ono, Koji
Nakai, Kazuo
Inatomi, Nobuhiro
Hori, Yasunobu
Matsukawa, Jun
Fujioka, Yasushi
Imanishi, Akio
Fukui, Hideo
Itoh, Fumio
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.
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Doi:10.1016/S0022-1139(00)82060-6
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