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	Yasuyoshi Arikawa, Haruyuki Nishida, Osamu Kurasawa, Atsushi Hasuoka, Keizo Hirase, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Akio Imanishi, Mitsuyo Kondo, Naoki Tarui, Teruki Hamada, Terufumi Takagi, Toshiyuki Takeuchi, Masahiro Kajino
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 9 Pg. 4446-56 (May 10 2012) ISSN: 1520-4804 [Electronic] United States
PMID	22512618 (Publication Type: Journal Article)
Chemical References	1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine Anti-Ulcer Agents Enzyme Inhibitors Fumarates Proton Pump Inhibitors Pyrroles Sulfonamides H(+)-K(+)-Exchanging ATPase
Topics	Animals Anti-Ulcer Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology) Dogs Enzyme Inhibitors (chemical synthesis, chemistry, pharmacokinetics, pharmacology) Fumarates (chemical synthesis, chemistry, pharmacokinetics) Gastric Mucosa (drug effects, metabolism) H(+)-K(+)-Exchanging ATPase (metabolism) Humans Inhibitory Concentration 50 Magnetic Resonance Spectroscopy Male Molecular Structure Peptic Ulcer (drug therapy, metabolism) Proton Pump Inhibitors Pyrroles (chemical synthesis, chemistry, pharmacology) Rats Rats, Sprague-Dawley Structure-Activity Relationship Sulfonamides (chemical synthesis, chemistry, pharmacology)

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