title: High-throughput screening of potassium-competitive acid blockers.
abstract: H(+),K(+)-ATPase is a key enzyme in the process of gastric acid secretion, and proton pump inhibitors (PPIs) have been accepted as one of the most effective treatments for peptic ulcer and gastroesophageal reflux disease. To discover a novel class of PPIs, the authors screened a low-molecular-weight compound library and identified two prospective acid blockers that were pyrrole derivatives. Both compounds inhibited H(+),K(+)-ATPase in a reversible and potassium-competitive manner. These compounds led to the development of TAK-438 (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate), which is currently undergoing clinical trials as a novel potassium-competitive acid blocker for the treatment of acid-related diseases.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kondo
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
mesh_terms: D000818:Animals; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D054328:Proton Pump Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D054852:Small Molecule Libraries; D013449:Sulfonamides; D017506:H(+)-K(+)-Exchanging ATPase