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)

Arikawa, Yasuyoshi; Nishida, Haruyuki; Kurasawa, Osamu; Hasuoka, Atsushi; Hirase, Keizo; Inatomi, Nobuhiro; Hori, Yasunobu; Matsukawa, Jun; Imanishi, Akihito; Kondo, Mitsuyo; Tarui, Naoki; Hamada, Takashi; Takagi, Terufumi; Takeuchi, Toshiyuki; Kajino, Masahiro

doi:10.1021/jm300318t

Cited by 130 publications

(75 citation statements)

References 32 publications

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“…Peripheral or central hypersensitivity in viscera is a potentially unifying pathophysiological concept in functional heartburn and reflux hypersensitivity. In Japan, vonoprazan, a novel and potent first-in-class P-CAB, was launched 5,6 and now is expected to prove useful even in the treatment of functional esophageal disorders triggered by acid hypersensitivity. 7 Functional esophageal disorders include functional chest pain (A1), functional heartburn (A2), reflux hypersensitivity (A3), globus (A4), and functional dysphagia (A5) in the Rome IV edition.…”

Section: Functional Esophageal Disordersmentioning

confidence: 99%

“…11 In the Rome IV section on FD, 5 only minor changes were introduced as compared to the previous Rome III criteria, 11 mainly to improve the specificity of the definition (Table). Among the major symptoms of FD, not only postprandial fullness, but also epigastric pain, epigastric burning, and early satiation should be "bothersome" symptoms.…”

Section: Functional Dyspepsiamentioning

confidence: 99%

“…It must include at least a discrete episode in the prior and 2 episodes in the past 6 months, occurring at least 1 week part. 5 It may combine with a family or past history of migraines. Meanwhile, CHS is absolutely distinct from CVS, as it exhibits different epidemiology, such as marijuana smoking, and has a specific pathological bathing behavior (prolonged hot baths or showers) and therapy.…”

Section: Nausea and Vomiting Disordersmentioning

confidence: 99%

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The Application of the Rome IV Criteria to Functional Esophagogastroduodenal Disorders in Asia

Suzuki

2017

J Neurogastroenterol Motil

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The Rome criteria were amended as Rome IV. For functional esophageal disorders, the exclusion criteria have been more specifically revised based on further understanding of other esophageal disorders, including eosinophilic esophagitis and spastic and hypercontractile motor disorders. Another revised point is the more restrictive definition of gastroesophageal reflux disease, indicating that sensitivity to a physiological reflux burden may be placed more firmly within the functional group. For functional dyspepsia (FD), only minor changes were introduced, mainly to improve specificity. Among the major symptoms of FD, not only postprandial fullness, but also epigastric pain, epigastric burning, and early satiation should be "bothersome." Investigation on the effect of meal ingestion on symptom generation has indicated that not only postprandial fullness and early satiety, but also epigastric pain, epigastric burning sensation and nausea (not vomiting) may increase after meals. Helicobacter pylori infection is considered a possible cause of dyspepsia if successful eradication leads to sustained resolution of symptoms for more than 6 months, and such status can be termed as "H. pylori-associated dyspepsia." Prompt esophagogastroduodenoscopy and H. pylori testing and treatment would be more beneficial, especially in Asia, which has a high prevalence of gastric cancer. Acotiamide, tandospirone, and rikkunshito are the newly listed as treatment options for FD. For further therapeutic development, clinical studies based on the strict Rome IV criteria should be performed.

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Section: Functional Esophageal Disordersmentioning

confidence: 99%

Section: Functional Dyspepsiamentioning

confidence: 99%

Section: Nausea and Vomiting Disordersmentioning

confidence: 99%

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The Application of the Rome IV Criteria to Functional Esophagogastroduodenal Disorders in Asia

Suzuki

2017

J Neurogastroenterol Motil

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“…Íåäàâíî ñèíòåçèðî-âàí åùå îäèí ïðåïàðàò äàííîãî ðÿäà -ïðîèçâîäíîå ïèððîëà ÒÀÊ-438, êîòîðûé îòëè÷àåòñÿ îò äðóãèõ Ð-CAB ìåäëåííîé ñêîðîñòüþ äèññîöèàöèè ñ ôåðìåí-òà. Â èññëåäîâàíèÿõ íà aeèâîòíûõ ÒÀÊ-438 îêàçàë áî-ëåå ìîùíîå è äëèòåëüíîå àíòèñåêðåòîðíîå äåéñòâèå, ïî ñðàâíåíèþ ñ äðóãèìè Ð-CAB è ëàíñîïðàçîëîì [8].…”

Section: áëîêàòîðû Kunclassified

Ингибиторы Протонового Насоса

Карева¹

2015

Эксп. и клин. фармакол.

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Îáçîð ëèòåðàòóðû ïîñâÿùåí ñðàâíèòåëüíîìó àíàëèçó ôàðìàêîëîãè÷åñêèõ ñâîéñòâ èíãèáèòîðîâ ïðîòîíîâîãî íàñîñà, øèðîêî èñïîëüçóåìûõ â ëå÷åíèè êèñëîòîçàâèñèìûõ çàáîëåâàíèé AEÊÒ. Â ñòàòüå ïîñëåäîâàòåëüíî ðàçîáðàíû âîïðîñû ôèçèîëîãè÷åñêîãî êîíòðîëÿ ïðîäóêöèè õëîðèñòîâîäîðîäíîé êèñëîòû â aeåëóäêå, ñòðîåíèå è ôóíêöèîíè-ðîâàíèå ïðîòîíîâîãî íàñîñà, ñðàâíèòåëüíûå õàðàêòåðèñòèêè ôàðìàêîëîãè÷åñêèõ ñâîéñòâ è îñîáåííîñòè êëèíè÷åñêîãî ïðèìåíåíèÿ èíãèáèòîðîâ ïðîòîíîâîãî íàñîñà.Êëþ÷åâûå ñëîâà: èíãèáèòîðû ïðîòîíîâîãî íàñîñà; ìåõàíèçì äåéñòâèÿ; êëèíè÷åñêàÿ ýôôåêòèâíîñòü; áåçîïàñíîñòü. ÂÂÅÄÅÍÈÅÈçáûòî÷íàÿ ïðîäóêöèÿ ñîëÿíîé êèñëîòû ÿâëÿåòñÿ ïðè÷èíîé ðàçâèòèÿ ðÿäà ïàòîëîãè÷åñêèõ ñîñòîÿíèé îðãàíîâ AEÊÒ. Òàêèå øèðîêî ðàñïðîñòðàíåííûå çàáî-ëåâàíèÿ êàê ÿçâåííàÿ áîëåçíü aeåëóäêà è äâåíàäöàòè-ïåðñòíîé êèøêè, ãàñòðîýçîôàãèòû, ôóíêöèîíàëüíàÿ äèñïåïñèÿ, ÍÏÂÏ-ãàñòðîïàòèè òðåáóþò â êà÷åñòâå ïà-òîãåíåòè÷åñêîé òåðàïèè èñïîëüçîâàíèÿ ïðåïàðàòîâ, ñíèaeàþùèõ êèñëîòíîñòü aeåëóäî÷íîãî ñîêà. Ê òàêèì ïðåïàðàòàì îòíîñÿòñÿ àíòàöèäû, àíòèãèñòàìèííûå ïðåïàðàòû è èíãèáèòîðû ïðîòîíîâîãî íàñîñà (ÈÏÍ). Ïðåïàðàòû ãðóïïû àíòàöèäîâ äàþò áûñòðûé, íî êðàò-êîâðåìåííûé ýôôåêò, êîòîðûé ìîaeåò ñîïðîâîaeäàòüñÿ ðàçâèòèåì ðÿäà íåãàòèâíûõ ýôôåêòîâ. Òàê, ïðè âçàè-ìîäåéñòâèè àëþìèíèÿ ãèäðîêñèäà, âõîäÿùåãî â ñîñòàâ àíòàöèäîâ, ñ êèñëîòîé â aeåëóäêå ìîaeåò âñàñûâàòüñÿ â êðîâü îò 17 äî 30 % îáðàçóþùåãîñÿ àëþìèíèÿ õëîðè-äà. Àíòèãèñòàìèííûå ïðåïàðàòû ïðè íåäîñòàòî÷íîé ýôôåêòèâíîñòè (òàõèôèëàêñèÿ) îáëàäàþò ðÿäîì ïî-áî÷íûõ ýôôåêòîâ, òàêèõ êàê êàðäèî-è ãåïàòîòîêñè÷-íîñòü. Íàèáîëåå âîñòðåáîâàííîé ãðóïïîé àíòèñåêðå-òîðíûõ ïðåïàðàòîâ ÿâëÿþòñÿ ÈÏÍ.Ìåõàíèçì äåéñòâèÿ ÈÏÍ. Êëþ÷åâîå çâåíî îáðàçî-âàíèÿ ñîëÿíîé êèñëîòû â aeåëóäêå -àêòèâíàÿ ñåêðå-öèÿ ïðîòîíîâ, ñîïðÿaeåííàÿ ñ àíòèïîðòîì K + , îñóùåñò-âëÿåòñÿ ñïåöèàëüíûì ìåìáðàííûì ôåðìåíòîì -ïðî-òîíîâûì íàñîñîì (H + , K + -ATÔaçà). Àêòèâíîñòü ïðîòî-íîâîãî íàñîñà êîíòðîëèðóåòñÿ ðàçëè÷íûìè ðåãóëÿòîðíûìè ôàêòîðàìè (àöåòèëõîëèíîì, ãèñòàìè-íîì, ãàñòðèíîì, ïðîñòàãëàíäèíàìè, ñîìàòîñòàòèíîì, ãàñòðîèíòåñòèíàëüíûìè òêàíåâûìè ôàêòîðàìè).Ïðîòîíîâûé íàñîñ íàõîäèòñÿ â ïàðèåòàëüíûõ êëåò-êàõ aeåëóäêà, ïëîòíîñòü êîòîðûõ âûñîêà â îáëàñòè äíà. Ïðîòîíîâûé íàñîñ îñóùåñòâëÿåò ïåðâè÷íî àêòèâíûé òðàíñïîðò èîíîâ âîäîðîäà â ïðîñâåò aeåëóäêà â îáìåí íà èîí K + , êîòîðûé âîçâðàùàåòñÿ â aeåëóäîê ÷åðåç K+ êàíàëû (KCNQ1) íà ëþìèíàëüíîé ïîâåðõíîñòè ïàðèå-òàëüíûõ êëåòîê. KCNE2 ñóáúåäèíèöà KCNQ1 àêòèâè-ðóåòñÿ ïðè ðÍ = 1,0, ïîääåðaeèâàÿ êàíàë â îòêðûòîì ñîñòîÿíèè [53]. Âíå ñòèìóëÿöèè ôåðìåíò íàõîäèòñÿ â öèòîïëàçìå ïàðèåòàëüíûõ êëåòîê â íåàêòèâíîé ôîðìå.Àêòèâàöèÿ ñåêðåöèè õëîðèñòîâîäîðîäíîé êèñëîòû ïðîèñõîäèò ïîä äåéñòâèåì ñèãíàëîâ, âûçûâàþùèõ ñëèÿíèå âåçèêóëÿðíûõ ìåìáðàí, â êîòîðûõ âñòðîåíû áåëêè ïðîòîíîâîãî íàñîñà, â ïëàçìàòè÷åñêóþ (ëþìè-íàëüíóþ) ìåìáðàíó, ãäå íàñîñ íà÷èíàåò ôóíêöèîíèðî-âàòü.Ëþáîé ñòèìóëÿòîð ïàðèåòàëüíûõ êëåòîê (ãèñòàìèí, ãàñòðèí, àöåòèëõîëèí) âûçûâàåò ïîâûøåíèå êîíöåí-òðàöèè âíóòðèêëåòî÷íîãî Ñà 2+

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“…6) We identified two lipophilic cavities (LP-1 and LP-2 sites) and two polar residues (Tyr925 and Tyr928) in the enzyme that could be used to improve inhibitory activity. 7,8) Figure 1 displays the docking model of compound 1 and also the target LP-1, LP-2 sites and two Tyr residues. This model suggested that this compound binds to the enzyme mainly via the LP-1 site (mode A).…”

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confidence: 99%

Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Arikawa

Hasuoka

Hirase

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.Key words potassium-competitive acid blocker (P-CAB); peptic ulcer; acid-related disease; 1H-pyrrolo [2,3-c]pyridine-7-amine; gastric acid secretion; gastroesophageal reflux disease (GERD) Current therapies for gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases either prevent the stimulation of parietal cells (e.g., H 2 receptor antagonists, H 2 RAs) or inhibit gastric H + /K + -ATPase (e.g., proton pump inhibitors, PPIs).1) Despite their potent inhibitory activities against acid secretion and their worldwide clinical application, it is suggested that the current treatment could be improved in several aspects.2) Potassium-competitive acid blockers (P-CABs), a new class of acid suppressants with a different mode of action from the existing therapies, are expected to offer some therapeutic benefits such as better symptom control and faster healing of GERD as well as other acid-related diseases.Over the past 30 years, various companies have focused on developing P-CABs as alternative acid suppressants.3)From our efforts to develop new P-CABs, we found a 1H-pyrrolo[2,3-c] pyridine-7-amine derivative 1 (Fig. 1, Left) has potent H + /K + -ATPase inhibitory activity (IC 50 27 nM). Recently, Panchal et al. also reported this compound and its derivatives as P-CABs.4) The acid secretion inhibitory activity in rats of this compound was 62% at the dose of 1 mg/kg on intravenous (i.v.) administration. This result encouraged us to explore more potent compounds in this derivative. In order to design potent inhibitors, we created the homology model of the luminal region of H + /K + -ATPase from the crystal structure of Ca 2+ -ATPase (PDB ID, 1IWO) 5) using SCWRL ver. 2.9. 6) We identified two lipophilic cavities (LP-1 and LP-2 sites) and two polar residues (Tyr925 and Tyr928) in the enzyme that could be used to improve inhibitory activity. 7,8) Figure 1 displays the docking model of compound 1 and also the target LP-1, LP-2 sites and two Tyr residues. This model suggested that this compound binds to the enzyme mainly via the LP-1 site (mode A).In order to improve the in vitro inhibitory activity, we used the following two strategies. First, the 7-position of PCABs has been considered as a possible target for improving inhibitory activity because the orthogonal conformation of benzyl substituents has a major impact on inhibitory activity in a series of imidazo[1,2-a] pyridine compounds.9) Next, we anticipated that the inhibitory activity could be improved via additional lipophilic and po...

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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)

Cited by 130 publications

References 32 publications

The Application of the Rome IV Criteria to Functional Esophagogastroduodenal Disorders in Asia

The Application of the Rome IV Criteria to Functional Esophagogastroduodenal Disorders in Asia

Ингибиторы Протонового Насоса

Molecular Modeling, Design, Synthesis, and Biological Activity of 1<i>H</i>-Pyrrolo[2,3-<i>c</i>]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

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