Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Nishida, Haruyuki; Arikawa, Yasuyoshi; Hirase, Keizo; Imaeda, Toshihiro; Inatomi, Nobuhiro; Hori, Yasunobu; Matsukawa, Jun; Fujioka, Yasushi; Hamada, Teruki; Iida, Motoo; Nishitani, Mitsuyoshi; Imanishi, Akio; Fukui, Hideo; Itoh, Fumio; Kajino, Masahiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 13(2017)
• Page Start: 3298
• Page End: 3314
• Publication Date: 2017-07-01
• Subjects: ADME-Tox absorption, distribution, metabolism, excretion, and toxicity -- CYP2C19 hepatic cytochrome P450 2C19 -- CYP3A4 hepatic cytochrome P450 3A4 -- DSC differential scanning calorimetry -- DIBAL-H diisobutylaluminium hydride -- DME 1, 2-dimethoxyethane -- DMF N, N-dimethylformamide -- DMPK drug metabolism and pharmacokinetics -- IC50 half-maximal inhibitory concentration -- HPLC high-performance liquid chromatography -- HRMS high-resolution mass spectrometry -- hERG human ether-a-go-go-related gene -- iv intravenous injection -- LLE ligand-lipophilicity efficiency -- LC/MS/MS liquid chromatography with tandem mass spectrometry -- LDA lithium diisopropylamide -- mp melting point -- MeO methoxy -- MS4Å molecular sieves 4 angstrom -- NCS N-chlorosuccinimide -- NMO N-methylmorpholine N-oxide -- PAMPA parallel artificial membrane permeability assay -- po per os -- P-CAB potassium-competitive acid blocker -- PPI proton pump inhibitor -- Py pyridyl -- RLU relative light units -- rt room temperature -- SAR structure-activity relationship -- THF tetrahydrofuran -- TG-DTA thermogravimetry-differential thermal analysis -- TLC thin-layer chromatography -- TsCl p-toluenesulfonyl chloride -- TPAP tetrapropylammonium perruthenate; H+, K+-ATPase -- Potassium-competitive acid blocker -- Fluoropyrrole -- Low lipophilicity -- Long duration of action; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 derivative1b 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 derivative37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower C log P and log D values than1b 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 compound1b in dogs. Therefore, compound37c can be considered a promising new P-CAB with long duration of action.