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1
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Nasu T, Hori A, Hotta N, Kihara C, Kubo A, Katanosaka K, Suzuki M, Mizumura K. Vacuolar-ATPase-mediated muscle acidification caused muscular mechanical nociceptive hypersensitivity after chronic stress in rats, which involved extracellular matrix proteoglycan and ASIC3. Sci Rep 2023; 13:13585. [PMID: 37604935 PMCID: PMC10442418 DOI: 10.1038/s41598-023-39633-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/28/2023] [Indexed: 08/23/2023] Open
Abstract
Although widespread pain, such as fibromyalgia, is considered to have a central cause, peripheral input is important. We used a rat repeated cold stress (RCS) model with many characteristics common to fibromyalgia and studied the possible involvement of decreased muscle pH in muscle mechanical hyperalgesia. After a 5-day RCS, the muscle pH and the muscular mechanical withdrawal threshold (MMWT) decreased significantly. Subcutaneously injected specific inhibitor of vacuolar ATPase (V-ATPase), bafilomycin A1, reversed both changes almost completely. It also reversed the increased mechanical response of muscle thin-fibre afferents after RCS. These results show that V-ATPase activation caused muscle pH drop, which led to mechanical hypersensitivity after RCS. Since extracellular matrix proteoglycan and acid sensitive ion channels (TRPV1 and ASIC3) have been considered as possible mechanisms for sensitizing/activating nociceptors by protons, we investigated their involvement. Manipulating the extracellular matrix proteoglycan with chondroitin sulfate and chondroitinase ABC reversed the MMWT decrease after RCS, supporting the involvement of the extracellular mechanism. Inhibiting ASIC3, but not TRPV1, reversed the decreased MMWT after RCS, and ASIC3 mRNA and protein in the dorsal root ganglia were upregulated, indicating ASIC3 involvement. These findings suggest that extracellular mechanism and ASIC3 play essential roles in proton-induced mechanical hyperalgesia after RCS.
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Affiliation(s)
- Teruaki Nasu
- Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan
| | - Amane Hori
- Graduate School of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan
- Japan Society for the Promotion of Science, Kojimachi, Chiyoda-Ku, Tokyo, 102-8472, Japan
| | - Norio Hotta
- Department of Lifelong Sports and Health Sciences, College of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan
| | - Chiaki Kihara
- Graduate School of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan
| | - Asako Kubo
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-Ku, Tokyo, 101-8310, Japan
- Department of Acupuncture and Moxibustion, Faculty of Rehabilitation, Niigata University of Health and Welfare, Niigata, 950-3198, Japan
| | - Kimiaki Katanosaka
- Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan
| | - Masamitsu Suzuki
- Central Research Laboratories, ZERIA Pharmaceutical Co. Ltd., 2512-1 Numagami, Oshikiri, Kumagaya, Saitama, 360-0111, Japan
| | - Kazue Mizumura
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-Ku, Tokyo, 101-8310, Japan.
- Department of Physical Therapy, College of Life and Health Sciences, Chubu University, Matsumoto-Cho, Kasugai, 487-8501, Japan.
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2
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Quantification of plant cardenolides by HPLC, measurement of Na +/K +-ATPase inhibition activity, and characterization of target enzymes. Methods Enzymol 2023; 680:275-302. [PMID: 36710014 DOI: 10.1016/bs.mie.2022.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The biosynthesis of cardiac glycosides, broadly classified as cardenolides and bufadienolides, has evolved repeatedly among flowering plants. Individual species can produce dozens or even hundreds of structurally distinct cardiac glycosides. Although all cardiac glycosides exhibit biological activity by inhibiting the function of the essential Na+/K+-ATPase in animal cells, they differ in their level of inhibitory activity. For within- and between-species comparisons of cardiac glycosides to address ecological and evolutionary questions, it is necessary to not only quantify their relative abundance, but also their effectiveness in inhibiting the activity of different animal Na+/K+-ATPases. Here we describe protocols for characterizing the amount and toxicity of cardenolides from plant samples and the degree of insect Na+/K+-ATPase tolerance to inhibition: (1) an HPLC-based assay to quantify the abundance of individual cardenolides in plant extracts, (2) an assay to quantify inhibition of Na+/K+-ATPase activity by plant extracts, and (3) extraction of insect Na+/K+-ATPases for inhibition assays.
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3
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Leowattana W, Leowattana T. Potassium-competitive acid blockers and gastroesophageal reflux disease. World J Gastroenterol 2022; 28:3608-3619. [PMID: 36161043 PMCID: PMC9372813 DOI: 10.3748/wjg.v28.i28.3608] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/24/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs), the most commonly used antisecretory medi-cations in the management of reflux illness, virtually eliminate elective surgery for ulcer disease, and relegate anti-reflux surgery to patients with gastroesophageal reflux disease (GERD) who are inadequately managed by medical therapy. However, PPI medications still leave some therapeutic demands of GERD unmet. Furthermore, up to 40%-55% of daily PPI users have chronic symptoms, due to PPI refractoriness. Potassium-competitive acid blockers (P-CABs) transcend many of the problems and limits of PPIs, delivering quick, powerful, and extended acid suppression and allowing for treatment of numerous unmet needs. Recently, it has become clear that compromised mucosal integrity plays a role in the etiology of GERD. As a result, esophageal mucosal protection has emerged as a novel and potential treatment approach. An increasing body of research demonstrates that when P-CABs are used as primary drugs or add-on drugs (to regular treatment), they provide a considerable extra benefit, particularly in alleviating symptoms that do not respond to PPI therapy.
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Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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4
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Tanaka S, Morita M, Yamagishi T, Madapally HV, Hayashida K, Khandelia H, Gerle C, Shigematsu H, Oshima A, Abe K. Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump. J Med Chem 2022; 65:7843-7853. [PMID: 35604136 DOI: 10.1021/acs.jmedchem.2c00338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.
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Affiliation(s)
- Saki Tanaka
- Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Mikio Morita
- Discovery Research, RaQualia Pharma Inc., 1-21-19 Meieki Minami, Nakamura, Nagoya 450-0003, Japan.,RaQualia Pharma Industry-Academia Collaborative Research Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Tatsuya Yamagishi
- Discovery Research, RaQualia Pharma Inc., 1-21-19 Meieki Minami, Nakamura, Nagoya 450-0003, Japan.,RaQualia Pharma Industry-Academia Collaborative Research Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Hridya Valia Madapally
- PHYLIFE: Physical Life Science, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
| | - Kenichi Hayashida
- Cellular and Structural Physiology Institute, Nagoya University, Nagoya, 464-8601, Japan
| | - Himanshu Khandelia
- PHYLIFE: Physical Life Science, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
| | - Christoph Gerle
- RIKEN SPring-8 Center, Kouto, Sayo-gun, Hyogo 679-5148, Japan.,Laboratory for Protein Crystallography, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
| | | | - Atsunori Oshima
- Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan.,Cellular and Structural Physiology Institute, Nagoya University, Nagoya, 464-8601, Japan.,Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, 464-8601, Japan
| | - Kazuhiro Abe
- Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan.,Cellular and Structural Physiology Institute, Nagoya University, Nagoya, 464-8601, Japan
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5
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Fujii T, Sugimoto K, Noda T, Shimizu T, Matsuya Y, Sakai H. Inhibition of gastric H +,K +-ATPase by new dihydropyrazole derivative KYY-008. Biochem Biophys Res Commun 2021; 567:177-182. [PMID: 34166915 DOI: 10.1016/j.bbrc.2021.06.056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
The gastric proton pump (H+,K+-ATPase) responsible for the H+ secretion of gastric acid is an essential therapeutic target for acid-related diseases. H+,K+-ATPase belongs to a P2-type ATPase family. Here, we examined the effects of a newly synthesized dihydropyrazole derivative KYY-008 on the H+,K+-ATPase. KYY-008 concentration-dependently inhibited the enzyme activity of the ATPase in the membrane fractions prepared from isolated hog gastric mucosa and from human kidney HEK293 cells in which gastric H+,K+-ATPase is exogenously expressed. The IC50 values in these samples were 3.4 μM and 3.7 μM, respectively. In addition, KYY-008 significantly inhibited the H+,K+-ATPase-derived H+ uptake into the tightly sealed vesicles prepared from the hog gastric mucosa. In contrast, KYY-008 has no effect on the activities of other P2-type ATPases such as Na+,K+-ATPase and Ca2+-ATPase. KYY-008 did not change the ionic currents of voltage-dependent Ca2+ channels, that were potential targets for some dihydropyrazole derivatives. Together, we discovered a new dihydropyrazole derivative which acts as a selective inhibitor of gastric H+,K+-ATPase.
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Affiliation(s)
- Takuto Fujii
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
| | - Kenji Sugimoto
- Department of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Takafumi Noda
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Takahiro Shimizu
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Yuji Matsuya
- Department of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Hideki Sakai
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
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Kim DK, Lee KH, Kim SJ, Kim SJ, Lee SJ, Park CH, Kim BT, Song GS, Moon BS, Ryu SY. Effects of Tegoprazan, a Novel Potassium-Competitive Acid Blocker, on Rat Models of Gastric Acid-Related Disease. J Pharmacol Exp Ther 2019; 369:318-327. [PMID: 30894456 DOI: 10.1124/jpet.118.254904] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/11/2019] [Indexed: 03/08/2025] Open
Abstract
Tegoprazan, a novel potassium-competitive acid blocker (P-CAB), is a next-generation therapeutics developed for the treatment of acid-related gastrointestinal diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. In the present study, the in vitro and in vivo pharmacological properties of tegoprazan were compared with those of esomeprazole, a representative proton pump inhibitor. In vitro enzyme assays were performed using ion-leaky vesicles containing gastric H+/K+-ATPases isolated from pigs. The in vivo efficacies of tegoprazan were evaluated in rat models of GERD and peptic ulcer. Tegoprazan inhibited the activity of porcine H+/K+-ATPase with an IC50 value of 0.53 μM in a reversible manner, whereas esomeprazole showed weak and irreversible inhibition with an IC50 value of 42.52 μM. In a GERD model, tegoprazan showed dose-dependent efficacy in inhibiting esophageal injury and gastric acid secretion with an ED50 of 2.0 mg/kg, which was 15-fold more potent than that of esomeprazole. In peptic ulcer models, tegoprazan exhibited superior antiulcer activity compared with esomeprazole. The ED50 of tegoprazan in the naproxen-, ethanol-, and water-immersion restraint stress-induced peptic ulcer models were 0.1, 1.4, and 0.1 mg/kg, respectively. In the acetic acid-induced peptic ulcer model, the curative ratio of tegoprazan at 10 mg/kg was higher than that of esomeprazole at 30 mg/kg (44.2% vs. 32.7%, respectively), after 5 days of repeated oral administration. Thus, tegoprazan is a novel P-CAB that shows potent and reversible inhibition of gastric H+/K+-ATPase and may provide stronger efficacy compared with previous proton pump inhibitors.
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Affiliation(s)
- Dong Kyu Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Keun-Ho Lee
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Sung-Jun Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Soo-Jin Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Song Jin Lee
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Chi Hye Park
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Bong-Tae Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
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7
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Takahashi N, Take Y. Tegoprazan, a Novel Potassium-Competitive Acid Blocker to Control Gastric Acid Secretion and Motility. J Pharmacol Exp Ther 2018; 364:275-286. [PMID: 29180359 DOI: 10.1124/jpet.117.244202] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 11/14/2017] [Indexed: 03/08/2025] Open
Abstract
Tegoprazan [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], a potassium-competitive acid blocker (P-CAB), is a novel potent and highly selective inhibitor of gastric H+/K+-ATPase. Tegoprazan inhibited porcine, canine, and human H+/K+-ATPases in vitro with IC50 values ranging from 0.29 to 0.52 μM, while that for canine kidney Na+/K+-ATPase was more than 100 μM. A kinetic analysis revealed that tegoprazan inhibited H+/K+-ATPase in a potassium-competitive manner and the binding was reversible. Oral single administrations of tegoprazan ranging from 0.3 to 30 mg/kg in dogs were well absorbed into the blood stream and distributed in gastric tissue/fluid higher than in plasma. Tegoprazan potently inhibited histamine-induced gastric acid secretion in dogs, and a complete inhibition was observed at 1.0 mg/kg starting from 1 hour after administration. Moreover, an oral administration of tegoprazan at 1 and 3 mg/kg reversed the pentagastrin-induced acidified gastric pH to the neutral range. Interestingly, 3 mg/kg tegoprazan immediately evoked a gastric phase III contraction of the migrating motor complex in pentagastrin-treated dogs and similar effects was observed with the other P-CAB, vonoprazan. Tegoprazan is the novel P-CAB that may provide a new option for the therapy of gastric acid-related and motility-impaired diseases.
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8
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Abstract
1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008)，a novel and potent potassium-competitive acid blocker for the treatment of acid secretion related diseases, has not been reported previously. In this study, we demonstrated that KFP-H008 inhibits basal acid secretion, 2-deoxy-D-glucose- (2DG-) stimulated gastric acid secretion in rats. KFP-H008 blocked histamine-stimulated acid secretion in rats and heidenhain pouch dogs and reversed acid output in isolated gastric perfusion under histamine stimulation. In all the animal experiments, KFP-H008 exerted a more effective, potent and longer-lasting inhibitory action in comparison with lansoprazole, a proton pump inhibitor (PPI) commonly used in clinic. KFP-H008 inhibited H+-K+-ATPase activity both at pH 6.5 and pH 7.5, and was unaffected by pH. The inhibitory action was reversible and was achieved in a K+-competitive manner. Furthermore, KFP-H008 did not affect Na+-K+-ATPase activity, thus exhibiting high selectivity, which is different from PPIs. In all, KFP-H008, a novel potassium-competitive acid blocker, may provide new option for the patients with acid-related diseases and provide longer-lasting inhibitory action than drugs commonly used in clinical treatment.
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Jo Y, Park E, Ahn SB, Jo YK, Son B, Kim SH, Park YS, Kim HJ. A Proton Pump Inhibitor's Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study. Gut Liver 2016; 9:607-14. [PMID: 25473078 PMCID: PMC4562777 DOI: 10.5009/gnl14135] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background/Aims Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. Methods We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. Results Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age ≥60 years was an independent predictor for the changes in serum calcium and urine DPD. Conclusions In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.
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Affiliation(s)
- Yunju Jo
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Eunkyoung Park
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Sang Bong Ahn
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Young Kwan Jo
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Byungkwan Son
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Seong Hwan Kim
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Young Sook Park
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Hyo Jeong Kim
- Division of Endocrinology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
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Keshipour S, Shaabani A, Shojaei S, Nosrati H, Ng SW. A novel one-pot isocyanide-based three-component reaction: synthesis of highly functionalized imidazo-chromen-4-ones. JOURNAL OF THE IRANIAN CHEMICAL SOCIETY 2015. [DOI: 10.1007/s13738-015-0640-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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11
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Arikawa Y, Hasuoka A, Nishida H, Hirase K, Inatomi N, Takagi T, Tarui N, Kawamoto M, Imanishi A, Itoh F, Kajino M. Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs). Bioorg Med Chem Lett 2015; 25:2037-40. [PMID: 25891103 DOI: 10.1016/j.bmcl.2015.03.094] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 03/26/2015] [Accepted: 03/31/2015] [Indexed: 11/25/2022]
Abstract
On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7, we prepared several five-membered heterocyclic analogues (8) and evaluated their H(+),K(+)-ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H(+),K(+)-ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.
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Affiliation(s)
- Yasuyoshi Arikawa
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
| | - Atsushi Hasuoka
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Haruyuki Nishida
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Keizo Hirase
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Nobuhiro Inatomi
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Terufumi Takagi
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Naoki Tarui
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Makiko Kawamoto
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Akio Imanishi
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Fumio Itoh
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Masahiro Kajino
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
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Rogoza LN, Salakhutdinov NF. Anti-ulcer agents: chemical aspect of solving the problem. RUSSIAN CHEMICAL REVIEWS 2015. [DOI: 10.1070/rcr4430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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13
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Zheng B, Hou W, Peng Y. Asymmetric oxa-Michael-aza-Henry Cascade Reaction of 2-Hydroxyaryl-Substituted α-Amido Sulfones and Nitroolefins Mediated by Chiral Squaramides. ChemCatChem 2014. [DOI: 10.1002/cctc.201402236] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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14
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Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K, Inatomi N, Hori Y, Matsukawa J, Imanishi A, Kondo M, Tarui N, Hamada T, Takagi T, Takeuchi T, Kajino M. 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). J Med Chem 2012; 55:4446-56. [PMID: 22512618 DOI: 10.1021/jm300318t] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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.
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Affiliation(s)
- Yasuyoshi Arikawa
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan.
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Hou W, Zheng B, Chen J, Peng Y. Asymmetric Synthesis of Polysubstituted 4-Amino- and 3,4-Diaminochromanes with a Chiral Multifunctional Organocatalyst. Org Lett 2012; 14:2378-81. [DOI: 10.1021/ol300798t] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Wenduan Hou
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China
| | - Bo Zheng
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China
| | - Jun Chen
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China
| | - Yungui Peng
- School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China
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Kim JH, Kim EH, Ock C, Hong H, Kim YJ, Kwon KA, Park DK, Hahm KB. Mitigating endoplasmic reticulum stress with revaprazan ameliorates stress-related mucosal disease. J Gastroenterol Hepatol 2012; 27:120-9. [PMID: 21722181 DOI: 10.1111/j.1440-1746.2011.06838.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIM The term "stress-related mucosal disease" (SRMD) represents conditions ranging from superficial mucosal damage to focal deep mucosal damage in the stomach, of which pathogenesis is deduced to be violent mucosal ischemia or excess oxidative stress, but not fully clarified yet. Under the hypothesis that mucosal cell apoptosis subsequent to endoplasmic reticulum (ER) stress might play a crucial role, we evaluated the efficacy and mechanism that novel acid pump antagonist (APA), revaprazan, alleviated water immersion restraint stress (WIRS) induced SRMD in rats. METHODS In order to define whether WIRS-induced SRMD is associated with ER stress, we checked the alteration in the expression of ER stress markers including GRP78, CHOP, XBP-1, BiP as well as apoptosis in WIRS-induced SRMD. The efficacy of revaprazan on either alleviating ER stress or attenuating SRMD was compared with proton pump inhibitor (PPI) and gastroprotectant. RESULTS Ten hours of WIRS induced a severe degree of SRMD, in which ER stress markers including CHOP, XBP1, and BiP were significantly overexpressed in the gastric tissues. However, these markers of ER stress were significantly decreased in the group pretreated with revaprazan compared to PPI or gastroprotectant, accompanied with a significant reduction in apoptotic index. In addition to ER stress, revaprazan imposed anti-inflammatory benefit to limit SRMD based on significant levels of inflammatory cell apoptosis. CONCLUSION Endoplasmic reticulum stress accompanied with drastic apoptosis was implicated in the development of SRMD, but revaprazan could rescue the stomach from SRMD through alleviating ER stress in epithelial cells much better than either PPI or gastroprotectant.
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Affiliation(s)
- Jung Ho Kim
- Department of Gastroenterology Gil Medical Center, Gachon Graduate School of Medicine, Incheon, Korea
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Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O, Sachs G. Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438). J Pharmacol Exp Ther 2011; 339:412-20. [PMID: 21828261 PMCID: PMC3199995 DOI: 10.1124/jpet.111.185314] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 08/08/2011] [Indexed: 12/20/2022] Open
Abstract
Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.
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Affiliation(s)
- Jai Moo Shin
- Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, 11301 Wilshire Blvd., Bldg. 113, CA 90073, USA.
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Ock CY, Lim YJ, Kim YJ, Chung JW, Kwon KA, Kim JH, Hahm KB. Acid pump antagonist-provoked HSP27 dephosphorylation and accentuation rescues stomach from indomethacin-induced damages. J Dig Dis 2011; 12:71-81. [PMID: 21401892 DOI: 10.1111/j.1751-2980.2011.00482.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Heat shock proteins (HSPs) are crucial for the maintenance of cellular integrity during normal cell growth as well as pathophysiological conditions. While acting as molecular chaperones with their folding activities, HSPs play a cytoprotective role to rescue epithelial cells from several gastric damages including non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori. Since the exact relationship between HSP27 phosphorylation and biological function remains unknown in NSAID-induced gastropathy, we hypothesized that revaprazan, a novel acid pump antagonist, can secure significant cytoprotection from NSAID damages through HSP27 accentuation. METHODS We evaluated protective actions of revaprazan against either in vivo animal model of indomethacin induced gastropathy or in vitro cell model focused on HSP27 expression and activation. RESULTS Indomethacin induced significant cytotoxicities accompanied with phosphorylated HSP27 and attenuated levels of HSP27 in the in vitro cell experiment and revaprazan administration protected stomach from indomethacin-induced gastric damages in accordance with HSP27 dephosphorylation in the in vivo animal experiment. HSP27 siRNA abolished these cytoprotective privileges of revaprazan. Indomethacin, 40 mg/kg, po, administration provoked significant levels of gastric damages accompanied with decrement in HSP27, while rats administrated with revaprazan prior to indomethacin imposed the accentuation of HSP27, of which levels were significantly correlated with the prevention of the indomethacin-induced gastric damages. CONCLUSION HSP27 phosphorylation with resultant decrease in HSP27 level was one of the mechanisms of indomethacin-induced cytotoxicity, of which post-translational modifications were prevented with revaprazan administration in the presence of indomethacin. Therefore, acid pump antagonist could be a choice for the prevention of NSAID-induced gastropathy backed up with distinctive cytoprotective action beyond acid suppressor.
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Affiliation(s)
- Chan Young Ock
- Lab of Translational Medicine, Gachon University Lee Gil Ya Cancer and Diabetes Institute, Incheon, Korea
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Alemán J, Núñez A, Marzo L, Marcos V, Alvarado C, García Ruano JL. Asymmetric synthesis of 4-amino-4H-chromenes by organocatalytic oxa-Michael/aza-Baylis-Hillman tandem reactions. Chemistry 2010; 16:9453-6. [PMID: 20661965 DOI: 10.1002/chem.201001293] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- José Alemán
- Departamento de Química Orgánica (C-I), Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain.
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