title: Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs).
abstract: On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7, 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, compound 7 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasuyoshi.arikawa@takeda.com.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Arikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Nishida
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Hirase
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
mesh_terms: D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure
chemical_list: D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D017506:H(+)-K(+)-Exchanging ATPase
keywords: Acid-related diseases; Gastroesophageal reflux disease; H(+),K(+)-ATPase; Peptic ulcer; Potassium-competitive acid blocker (P-CAB)