Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs). Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Arikawa, Yasuyoshi; Hasuoka, Atsushi; Nishida, Haruyuki; Hirase, Keizo; Inatomi, Nobuhiro; Takagi, Terufumi; Tarui, Naoki; Kawamoto, Makiko; Imanishi, Akio; Itoh, Fumio; Kajino, Masahiro
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 10(2015)
• Page Start: 2037
• Page End: 2040
• Publication Date: 2015-05-15
• Subjects: Potassium-competitive acid blocker (P-CAB) -- H+, K+-ATPase -- Gastroesophageal reflux disease -- Peptic ulcer -- Acid-related diseases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.094
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative7, we prepared several five-membered heterocyclic analogues (8 ) and evaluated their H +, K + -ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H +, K + -ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.