Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Nishida, Haruyuki; Fujimori, Ikuo; Arikawa, Yasuyoshi; Hirase, Keizo; Ono, Koji; Nakai, Kazuo; Inatomi, Nobuhiro; Hori, Yasunobu; Matsukawa, Jun; Fujioka, Yasushi; Imanishi, Akio; Fukui, Hideo; Itoh, Fumio
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 13(2017)
• Page Start: 3447
• Page End: 3460
• Publication Date: 2017-07-01
• Subjects: ADME-Tox absorption, distribution, metabolism, excretion, and toxicity -- AUC area under the curve -- BnSH benzyl mercaptan -- Xantphos 4, 5-bis(diphenylphosphino)-9, 9-dimethylxanthene -- CYP2C19 hepatic cytochrome P450 2C19 -- CYP3A4 hepatic cytochrome P450 3A4 -- DBU 1, 8-diazabicyclo[5.4.0]undec-7-ene -- DSC differential scanning calorimetry -- DMB 2, 4-dimethoxybenzyl -- DMAP 4-dimethylaminopyridine -- DMSO dimethyl sulfoxide -- Boc2O di-tert-butyl dicarbonate -- DMPK drug metabolism and pharmacokinetics -- ESI electrospray ionization -- 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 -- LC/MS/MS liquid chromatography with tandem mass spectrometry -- LDA lithium diisopropylamide -- mp melting point -- MeO methoxy -- NCS N-chlorosuccinimide -- po er os -- P-CAB potassium-competitive acid blocker -- PPI proton pump inhibitor -- Py pyridyl -- rt room temperature -- THF tetrahydrofuran -- TG-DTA thermogravimetrydifferential thermal analysis -- TLC thin-layer chromatography; Potassium-competitive acid blocker -- Transfer behavior to the stomach -- Rapid onset -- Moderately long-lasting acid suppression; 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.2017.04.034
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger C log P value (1.95), larger log D value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound2a, compound20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound20j was selected as a new promising P-CAB with moderately long duration of action.