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.
MeSH terms
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Animals
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Anti-Ulcer Agents / chemical synthesis
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Anti-Ulcer Agents / chemistry*
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Anti-Ulcer Agents / pharmacokinetics
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Anti-Ulcer Agents / pharmacology*
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Dogs
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Fumarates / chemical synthesis
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Fumarates / chemistry
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Fumarates / pharmacokinetics
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Gastric Mucosa / drug effects
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Gastric Mucosa / metabolism
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H(+)-K(+)-Exchanging ATPase / metabolism
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Humans
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Male
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Molecular Structure
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Peptic Ulcer / drug therapy
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Peptic Ulcer / metabolism
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Proton Pump Inhibitors*
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
Substances
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1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine
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Anti-Ulcer Agents
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Enzyme Inhibitors
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Fumarates
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Proton Pump Inhibitors
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Pyrroles
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Sulfonamides
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H(+)-K(+)-Exchanging ATPase