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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)
- Source :
- Journal of Medicinal Chemistry. 55:4446-4456
- Publication Year :
- 2012
- Publisher :
- American Chemical Society (ACS), 2012.
-
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.
- Subjects :
- Male
Peptic Ulcer
Magnetic Resonance Spectroscopy
Stereochemistry
Potassium
chemistry.chemical_element
Pyrrole derivatives
Rats, Sprague-Dawley
H(+)-K(+)-Exchanging ATPase
Inhibitory Concentration 50
Structure-Activity Relationship
Dogs
Fumarates
In vivo
Drug Discovery
medicine
Animals
Humans
Structure–activity relationship
Pyrroles
Enzyme Inhibitors
Sulfonamides
Molecular Structure
Chemistry
Drug candidate
Proton Pump Inhibitors
Nuclear magnetic resonance spectroscopy
Anti-Ulcer Agents
medicine.disease
Rats
Gastric Mucosa
Peptic ulcer
Molecular Medicine
Gastric acid
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 55
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....11eb3b6a9b221556449e78c91290c08b