title: Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB).
abstract: In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan. yasuyoshi.arikawa@takeda.com
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Arikawa
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Nishida
authors.forename: Osamu
authors.initials: O
authors.lastname: Kurasawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
authors.forename: Keizo
authors.initials: K
authors.lastname: Hirase
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hori
authors.forename: Jun
authors.initials: J
authors.lastname: Matsukawa
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kondo
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Teruki
authors.initials: T
authors.lastname: Hamada
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005650:Fumarates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010437:Peptic Ulcer / Q000188:drug therapy / Q000378:metabolism; D054328:Proton Pump Inhibitors; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D005650:Fumarates; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D017506:H(+)-K(+)-Exchanging ATPase