WikiJournal Preprints/Discovery and development of proton pump inhibitors

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Article information

Abstract

w:Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.


Introduction

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History

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Evidence emerged by the end of the 1970s that the newly discovered proton pump (H+/K+ ATPase) in the secretory membrane of the parietal cell was the final step in acid secretion.[1] Literature from anaesthetic screenings led attention to the potential antiviral compound pyridylthioacetamide which after further examination pointed the focus on an anti-secretory compound with unknown mechanisms of action called timoprazole.[2][3] Timoprazole is a pyridylmethylsulfinyl benzimidazole and appealed due to its simple chemical structure and its surprisingly high level of anti-secretory activity.[4]

Optimization of substituted benzimidazoles and their antisecretory effects were studied on the newly discovered proton pump to obtain higher pKa values of the pyridine, thereby facilitating accumulation within the parietal cell and increasing the rate of acid-mediated conversion to the active mediate. As a result of such optimization the first proton pump inhibiting drug, omeprazole, was released on the market.[5] Other PPIs such as lansoprazole and pantoprazole would follow in its footsteps, claiming their share of a flourishing market, after their own course of development.

Basic structure

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PPIs can be divided into two groups based on their basic structure. Although all members have a substituted pyridine part, one group has it linked to various benzimidazoles but the other has it linked to a substituted imidazopyridine. All marketed PPIs such as omeprazole, lansoprazole, pantoprazole are in the benzimidazole group.

Proton pump inhibitors are prodrugs and their actual inhibitory form is somewhat controversial. In acidic solution, the sulfenic acid is isolated before reaction with one or more cysteines accessible from the luminar surface of the enzyme, a tetracyclic sulfenamide. This is a planar molecule thus any enantiomer of a PPI loses stereospecifity upon activation.[6]

The effectiveness of these drugs derives from two factors: their target, the H+/K+ ATPase which is responsible for the last step in acid secretion; therefore, their action on acid secretion is independent of the stimulus to acid secretion, of histamine, acetylcholine, or other yet to be discovered stimulants. In addition, their mechanism of action involves covalent binding of the activated drug to the enzyme, resulting in a duration of action that exceeds their plasma half-life.[7]

The gastric ATPase

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Acid secretion by the human stomach results in a median diurnal pH of 1.4. This very large (>106-fold) H+ gradient is generated by the gastric H+/K+ ATPase which is an ATP-driven proton pump. Hydrolysis of one ATP molecule is used to catalyse the electroneutral exchange of two luminal potassium ions for two cytoplasmic protons through the gastric membrane.[8]

Structure

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The proton pump, H+/K+ ATPase is a α,β-heterodimeric enzyme. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5, TM6 and TM8. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven N-linked glycosylation sites which is important for the enzyme assembly, maturation and sorting.[9]

Function

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The ion transport is accomplished by cyclical conformational changes of the enzyme between its two main reaction states, E1 and E2. The cytoplasmic-open E1 and luminal-open E2 states have high affinity for H+ and K+.[9] The expulsion of the proton at 160 mM (pH 0.8) concentration results from movement of lysine 791 into the ion binding site in the E2P configuration.[10]

PPIs binding mode

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The disulfide binding of the inhibitor takes place in the luminal sector of the H+/K+ ATPase were 2 mol of inhibitor is bound per 1 mol of active site H+/K+ ATPase.[19][20] All PPIs react with cysteine 813 in the loop between TM5 and TM6 on the H+/K+ ATPase, fixing the enzyme in the E2 configuration. Omeprazole reacts with cysteine 813 and 892. Rabeprazole binds to cysteine 813 and both 892 and 321. Lansoprazole reacts with cysteine 813 and cysteine 321, whereas pantoprazole and tenatoprazole react with cysteine 813 and 822.[18][21][22][23] Reaction with cysteine 822 confers a rather special property to the covalently inhibited enzyme, namely irreversibility to reducing agents. The likely first step is binding of the prodrug protonated on the pyridine of the compound with cysteine 813. Then the second proton is added with acid transport by the H+/K+ ATPase, and the compound is activated. Recent data suggest the hydrated sulfenic acid to be the reactive species forming directly from the mono-protonated benzimidazole bound on the surface of the pump.[7]

Saturation of the gastric ATPase

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Even though consumption of food stimulates acid secretion and acid secretion activates PPIs, PPIs cannot inhibit all pumps. About 70% of pump enzyme is inhibited, as PPIs have a short half-life and not all pump enzymes are activated. It takes about 3 days to reach steady-state inhibition of acid secretion, as a balance is struck between covalent inhibition of active pumps, subsequent stimulation of inactive pumps after the drug has been eliminated from the blood, and de novo synthesis of new pumps.[8]

Discovery

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In the year 1975, timoprazole was found to inhibit acid secretion irrespective of stimulus, extracellular or intracellular.[7] Studies on timoprazole revealed enlargement of the thyroid gland due to inhibition of iodine uptake as well as atrophy of the thymus gland. A literature search showed that some substituted mercapto-benzimidazoles had no effect on iodine uptake and introduction of such substituents into timoprazole resulted in an elimination of the toxic effects, without reducing the antisecretory effect.[6] A derivative of timoprazole, omeprazole, was discovered in 1979, and was the first of a new class of drug that control acid secretion in the stomach, a proton pump inhibitor (PPI).[11][12] Addition of 5-methoxy-substitution to the benzimidazole moiety of omeprazole was also made and gave the compound much more stability at neutral pH.[6] In 1980, an Investigational New Drug (IND) application was filed and omeprazole was taken into Phase III human trials in 1982.[6] A new approach for the treatment of acid-related diseases was introduced, and omeprazole was quickly shown to be clinically superior to the histamine H2 receptor antagonists, and was launched in 1988 as Losec in Europe, and in 1990 as Prilosec in the United States. In 1996, Losec became the world's biggest ever selling pharmaceutical, and by 2004 over 800 million patients had been treated with the drug worldwide. During the 1980s, about 40 other companies entered the PPIs area, but few achieved market success: Takeda with lansoprazole, Byk Gulden (now Nycomed) with pantoprazole, and Eisai with rabeprazole, all of which were analogues of omeprazole.[7][8]

Development

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Clinical pharmacology

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Although the drugs omeprazole, lansoprazole, pantoprazole, and rabeprazole share common structure and mode of action, each differs somewhat in its clinical pharmacology.[24] Differing pyridine and benzimidazole substituents result in small, but potentially significant different physical and chemical properties. Direct comparison of pantoprazole sodium with other anti-secretory drugs showed that it was significantly more effective than H2-receptor antagonists and either equivalent or better than other clinically used PPIs.[5] Another study states rabeprazole undergoes activation over a greater pH range than omeprazole, lansoprazole, and pantoprazole, and converts to the sulphenamide form more rapidly than any of these three drugs.[23] Most oral PPI preparations are enteric-coated, due to the rapid degradation of the drugs in the acidic conditions of the stomach. For example omeprazole is unstable in acid with a half-life of 2 min at pH 1–3, but is significantly more stable at pH 7 (half-life ca. 20 h). The acid protective coating prevents conversion to the active principle in the lumen of the stomach, which then will react with any available sulfhydryl group in food and will not penetrate to the lumen of the secretory canaliculus[10]

The oral bioavailability of PPIs is high; 77% for pantoprazole, 80–90% for lansoprazole and 89% for esomeprazole. All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes, mostly by CYP2C19 and CYP3A4. PPIs are sensitive to CYP enzymes and have different pharmacokinetic profiles. Studies comparing the efficacy of PPIs indicate that esomeprazole and tenatoprazole have stronger acid suppression, with a longer period of intragastric pH (pH > 4).[25][26][27][28][29]

Studies of the effect of tenatoprazole on acid secretion in in vivo animal models, such as pylorus-ligated rats and acute gastric fistula rats, demonstrated a 2- to 4-fold more potent inhibitory activity compared with omeprazole. A more potent inhibitory activity was also shown in several models of induced gastric lesions.[30] In Asian as well as Caucasian healthy subjects, tenatoprazole exhibited a seven-fold longer half-life than the existing H+/K+ ATPase inhibitors.[31] It is thus hypothesized that a longer half-life results in a more prolonged inhibition of gastric acid secretion, especially during the night. A strong relationship has been stated between the degree and duration of gastric acid inhibition, as measured by monitoring of the 24-hour intragastric pH in pharmacodynamic studies, and the rate of healing and symptom relief reported. A clinical study showed that nocturnal acid breakthrough duration was significantly shorter for 40 mg of tenatoprazole than for 40 mg of esomeprazole, with the conclusion that tenatoprazole was significantly more potent than esomeprazole during the night. Although, the therapeutic relevance of this pharmacological advantage deserves further study.[17]

PPIs have been used successfully in triple-therapy regiments with clarithromycin and amoxicillin for the eradication of Helicobacter pylori with no significant difference between different PPI-based regimens.[10]

Future research and new generations of PPIs

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Potassium-competitive acid blockers or acid pump antagonists

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Even though PPIs have revolutionized the treatment of GERD, there is still room for improvement in the speed of onset of acid suppression as well as mode of action that is independent of an acidic environment and also better inhibition of the proton pump.[8] Therefore, a new class of PPIs, potassium-competitive acid blockers (P-CABs) or acid pump antagonists (APAs), have been under development the past years and will most likely be the next generation of drugs that suppress gastric activity.[32] These new agents can in a reversible and competitive fashion inhibit the final step in the gastric acid secretion with respect to K+ binding to the parietal cell gastric H+/K+ ATPase. That is, they block the action of the H+/K+ ATPase by binding to or near the site of the K+ channel. Since the binding is competitive and reversible these agents have the potential to achieve faster inhibition of acid secretion and longer duration of action compared to PPIs, resulting in quicker symptom relief and healing.[33][34] The imidazopyridine-based compound SCH28080 was the prototype of this class, and turned out to be hepatotoxic.[35] Newer agents that are currently in development include CS-526, linaprazan, soraprazan and revaprazan in which the latter have reached clinical trials. Studies remain to determine whether these or other related compounds can become useful.[34][36] In June 2006, Yuhan obtained approval from the Korean FDA for the use of revaprazan (brand name Revanex) in the treatment of gastritis.[37]

Additional information

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Acknowledgements

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Any people, organisations, or funding sources that you would like to thank.

Competing interests

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Any conflicts of interest that you would like to declare. Otherwise, a statement that the authors have no competing interest.

Ethics statement

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An ethics statement, if appropriate, on any animal or human research performed should be included here or in the methods section.

References

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  1. Forte, J. G.; Lee, H. C. (1977-10). "Gastric adenosine triphosphatases: a review of their possible role in HCl secretion". Gastroenterology 73 (4 Pt 2): 921–926. ISSN 0016-5085. PMID 20386. https://www.ncbi.nlm.nih.gov/pubmed/20386. 
  2. Hemenway, Jeffrey N. (2007). Stella, Valentino J.. ed. Prodrugs (in en). V. New York, NY: Springer New York. pp. 1313–1321. doi:10.1007/978-0-387-49785-3_49. ISBN 9780387497822. http://link.springer.com/10.1007/978-0-387-49785-3_49. 
  3. Olbe, Lars; Carlsson, Enar; Lindberg, Per (2003-2). "A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole". Nature Reviews. Drug Discovery 2 (2): 132–139. doi:10.1038/nrd1010. ISSN 1474-1776. PMID 12563304. https://www.ncbi.nlm.nih.gov/pubmed/12563304. 
  4. Senn-Bilfinger, Jörg; Sturm, Ernst (2006-06-21). Fischer, János. ed. Analogue-based Drug Discovery. Weinheim, FRG: Wiley-VCH Verlag GmbH & Co. KGaA. pp. 115–136. doi:10.1002/3527608001.ch6. ISBN 9783527608003. http://doi.wiley.com/10.1002/3527608001.ch6. 
  5. Lindberg, Per; Carlsson, Enar (2006-06-21). Fischer, János. ed. Analogue-based Drug Discovery. Weinheim, FRG: Wiley-VCH Verlag GmbH & Co. KGaA. pp. 81–113. doi:10.1002/3527608001.ch5. ISBN 9783527608003. http://doi.wiley.com/10.1002/3527608001.ch5. 
  6. Shin, Jai Moo; Munson, Keith; Vagin, Olga; Sachs, George (2009-1). "The gastric HK-ATPase: structure, function, and inhibition". Pflugers Archiv: European Journal of Physiology 457 (3): 609–622. doi:10.1007/s00424-008-0495-4. ISSN 0031-6768. PMID 18536934. PMC 3079481. https://www.ncbi.nlm.nih.gov/pubmed/18536934. 
  7. Sachs, George; Shin, Jai Moo; Vagin, Olga; Lambrecht, Nils; Yakubov, Iskandar; Munson, Keith (2007-7). "The gastric H,K ATPase as a drug target: past, present, and future". Journal of Clinical Gastroenterology 41 Suppl 2: S226–242. doi:10.1097/MCG.0b013e31803233b7. ISSN 0192-0790. PMID 17575528. PMC 2860960. https://www.ncbi.nlm.nih.gov/pubmed/17575528. 
  8. Abe, Kazuhiro; Tani, Kazutoshi; Nishizawa, Tomohiro; Fujiyoshi, Yoshinori (2009-06-03). "Inter-subunit interaction of gastric H+,K+-ATPase prevents reverse reaction of the transport cycle". The EMBO journal 28 (11): 1637–1643. doi:10.1038/emboj.2009.102. ISSN 1460-2075. PMID 19387495. PMC 2693145. https://www.ncbi.nlm.nih.gov/pubmed/19387495. 
  9. Shin, Jai Moo; Sachs, George (2008-12). "Pharmacology of proton pump inhibitors". Current Gastroenterology Reports 10 (6): 528–534. doi:10.1007/s11894-008-0098-4. ISSN 1534-312X. PMID 19006606. PMC 2855237. https://www.ncbi.nlm.nih.gov/pubmed/19006606.