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Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action
- Source :
- Bioorganicmedicinal chemistry. 25(13)
- Publication Year :
- 2017
-
Abstract
- With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.
- Subjects :
- 0301 basic medicine
Drug
Stereochemistry
Cell Survival
media_common.quotation_subject
Potassium
Clinical Biochemistry
Lansoprazole
Pharmaceutical Science
chemistry.chemical_element
Administration, Oral
Biochemistry
PH elevation
Gastric Acid
03 medical and health sciences
chemistry.chemical_compound
H(+)-K(+)-Exchanging ATPase
Structure-Activity Relationship
Dogs
Drug Discovery
medicine
Animals
Humans
Pyrroles
Molecular Biology
Pyrrole
media_common
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
Proton Pump Inhibitors
Hep G2 Cells
Hydrogen-Ion Concentration
Combinatorial chemistry
Ether-A-Go-Go Potassium Channels
Rats
030104 developmental biology
HEK293 Cells
chemistry
Lipophilicity
Molecular Medicine
Lead compound
Derivative (chemistry)
medicine.drug
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 25
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....5bac684f5eccfc18c3228e16d7323bb0