Bioorganic & Medicinal Chemistry 15 (2007) 1181–1205
`
`Review
`
`Recent advances in proton pump inhibitors and management
`of acid-peptic disorders
`
`Kishor S. Jain,a,* Anamik K. Shah,b Jitender Bariwal,b Suhas M. Shelke,a
`Amol P. Kale,c Jayshree R. Jagtapc and Ashok V. Bhosalec
`aSinhgad College of Pharmacy, Pune 411 041, India
`bDepartment of Chemistry, Saurashtra University, Rajkot 360 005, India
`cSGRS College of Pharmacy, Saswad, Pune 412 301, India
`
`Received 22 June 2006; revised 30 July 2006; accepted 31 July 2006
`Available online 5 December 2006
`
`Abstract—Acid-peptic ulcers and diseases have been increasingly on rise in today’s era of globalization, which is characterized by
`hurry, worry, and curry. This review summarizes various disorders associated with increased gastric acid secretion and various ther-
`apeutic strategies to control them. The emphasis has been laid, in particular, on the role of proton pump inhibitors (PPIs) widely
`used nowadays for the treatment of gastric acid diseases. The medicinal chemistry aspects and mechanism of action of irreversible
`PPIs and APAs have been discussed at molecular levels. The ongoing research status in this field has also been covered. Further,
`biological evaluation methods that can be used for screening of PPIs are also discussed in short.
`Ó 2006 Elsevier Ltd. All rights reserved.
`
`Contents
`
`1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182
`1.1. Mechanism of gastric acid secretion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183
`1.2. Disorders associated with elevated secretion of gastric acid . . . . . . . . . . . . . . . . . . . . . . . . 1183
`1.3. Complications arising from the disorders associated with elevated secretion of gastric acid . . 1185
`1.3.1. Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
`1.3.2. Hemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
`1.3.3. Malignant transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
`1.3.4. Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
`2. Therapeutic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
`2.1. Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
`2.2. Muscarinic antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
`2.3. H2 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
`2.4. Eradication of H. pylori infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187
`2.5. Other agents used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187
`2.6. Proton pump inhibitors (PPIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188
`3. Structure of the proton pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188
`4. Classification of PPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189
`4.1.
`Irreversible gastric PPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189
`4.1.1. Pyridinylmethylsulfinyl benzimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
`4.1.2. Pyridylmethylsulfinyl thienoimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
`4.1.3. Aminobenzylsulfinyl benzimidazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
`4.2. Reversible gastric PPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
`
`Keywords: Acid-peptic disorders; Therapeutic strategies; Gastric H+/K+-ATPase (proton pump); Proton pump inhibitors (PPIs); Acid pump
`antagonist (APAs).
`* Corresponding author. Tel./fax: +91 20 24354720; e-mail addresses: ks_jain@vsnl.net; ks_jainin@yahoo.co.in
`
`0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.bmc.2006.07.068
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 1 of 25
`
`

`

`1182
`
`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`5. Irreversible proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
`5.1.
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
`5.2. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
`5.3.
`Structure–activity relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192
`5.4. Drawbacks of irreversible proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
`5.5. Pharmacological properties of the PPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
`6. Reversible proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
`6.1.
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
`6.2. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
`6.3.
`Structure–activity relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
`7. Reports on the ongoing research and development on different PPIs as well as other agents . . . . . 1194
`7.1.
`Irreversible inhibitors, related structurally to pyridinylmethylsulfinyl benzimidazole . . . . . . . 1194
`7.1.1. Changes made on/in the benzimidazole nucleus. . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
`7.1.2. Changes made on the pyridine nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
`Irreversible inhibitors, not related structurally to pyridinylmethylsulfinyl benzimidazole . . . . 1196
`7.2.
`7.3. Reversible inhibitors (acid pump antagonists) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1196
`7.4. Other proton pump inhibitors under investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199
`7.5.
`Some more literature reports. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
`7.5.1. CCK2/gastrin-receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8. Biological evaluation of PPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.1.
`Studies on isolated guinea pig mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.1.1. Preparation of tissue and solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.1.2. Measurement of H+ secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.1.3. Measurement of K+ secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.1.4. Experiments with simultaneous measurements of K+ and H+ secretion . . . . . . . . . . 1201
`8.2. Effect of H+/K+ ATPase inhibitors on serum gastrin levels . . . . . . . . . . . . . . . . . . . . . . . . 1201
`8.3. Pylorus Ligation in rats (Shay et al.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
`9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
`Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
`References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
`
`1. Introduction
`
`‘Hurry, Worry & Curry’ are the causes of many disor-
`ders in today’s world of globalization. Of these acid-
`peptic ulcers and diseases have assumed a distinctly high
`proportion. The pathophysiology of acid-peptic disease
`is attributed to the imbalance between aggressive factors
`(like acid, pepsin, and Helicobacter pylori infection) and
`local mucosal defenses (like secretion of bicarbonate,
`mucus, and prostaglandins). Although treatment is of-
`ten directed at reduction of aggressive factors, it can also
`be directed at strengthening mucosal defenses of stom-
`ach and duodenum.1
`
`The inhibition of gastric acid secretion is a key therapeu-
`tic target for the ulcer diseases (viz., peptic, duodenal ul-
`cers or
`that
`through H. pylori
`infection), gastro
`esophageal reflux disease (GERD), Zollinger–Ellison
`syndrome (Z-E), and gastritis. Currently this is achieved
`
`by blocking the acid secretary effect of histamine (HA)
`through the use of H2-receptor antagonists or the irre-
`versible H+/K+-ATPase inhibitors, popularly referred
`to as proton pump inhibitors (PPIs). The incidence of
`ulcer diseases shows global variation and their treatment
`should be designed to alleviate the symptoms, while
`keeping the risk of adverse effects to minimum. In wes-
`tern countries duodenal ulcers are more common,
`whereas in eastern countries gastric ulcers predominate.
`These differences are attributed to factors like diet and
`genetic make up. As a result the therapeutic strategies
`also differ from east to west. In western countries, the
`conventional therapy for duodenal and gastric ulcer is
`eradication of H. pylori. Whereas, in Japan unlike the
`west, H2-antagonists are commonly used for mainte-
`nance therapy along with the PPIs.2
`
`The discovery of the gastric acid was the first step to
`understand the role of the stomach in digestion and
`
`Table 1. Some landmarks in the therapy of acid-peptic disorders in past 35 years2
`
`Year
`
`1972
`1973
`1976
`1982
`1988
`1995
`1997
`2001
`
`Company/discoverer
`
`James Black et al.5
`A. Ganser & J. Forte.6
`SmithKline & French.7
`Allen & Hanburys Ltd8
`AstraZeneca.9
`Takeda-Abbott10
`Eisai Co. (licensed to Janssen)11
`AstraZeneca12
`
`Event/discovery
`
`Discovery of H2-receptor and H2-receptor antagonists
`Discovery of H+/K+-ATPase (The Proton Pump)
`Cimetidine launched (H2-receptor antagonist)
`Ranitidine launched (H2-receptor antagonist)
`Omeprazole launched (PPI)
`Lansoprazole launched (PPI)
`Rabeprazole launched (PPI)
`Esomeprazole launched (PPI)
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 2 of 25
`
`

`

`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`1183
`
`the diseases associated with hypersecretion of acid.3,4
`The drug discovery process linked with the gastric acid
`secretion involving H2-receptor antagonists and PPIs is
`summarized in Table 1. It indicates the gradual change
`in the focus in the treatment of gastric acid secretion
`disorders.2
`
`In this review, various disorders related with increased
`gastric acid secretion and therapeutic strategies to con-
`trol them have been summarized. Furthermore, empha-
`sis has been laid on the role of PPIs in particular for the
`treatment of gastric acid disorders. The medicinal chem-
`istry aspects of this particular class of compounds are
`also discussed.
`
`1.1. Mechanism of gastric acid secretion
`
`Stomach is a primary site of digestion. Presence of food
`stimulates release of acids and enzymes in stomach. The
`chemo- and mechanosensitive receptors present in stom-
`ach are triggered by presence of food to produce specific
`responses.2 The acid secreting parietal cell is the princi-
`ple cell in gastric glands. The physiological regulation of
`acid secretion by the parietal cells is thus an important
`factor behind the rationale of use of various agents to
`reduce gastric acidity. Three major pathways activating
`parietal acid secretion include: (1) neuronal stimulation
`via the vagus nerve, (2) paracrine stimulation by local
`release of histamine from enterochromaffin-like (ECL)
`cells, and (3) endocrine stimulation via gastrin released
`from antral G cells. In neuronal pathway, acetylcholine
`(Ach) released by vagal nerve directly stimulates gastric
`acid secretion through muscarinic M3 receptors located
`on the basolateral membrane of parietal cells. The
`CNS is considered to be the chief contributor for initiat-
`ing gastric acid secretion in response to the anticipation
`of food. Ach indirectly stimulates release of histamine
`from enterochromaffin-like (ECL) cells in the fundus
`and gastrin from the G cells in the gastric antrum.
`ECL cells, the sole source of gastric histamine involved
`in acid secretion, are present in close proximity to pari-
`etal cells. Histamine released from ECL cells activates
`parietal cells in paracrine fashion by binding to H2
`receptors. Gastrin is primarily present in antral G cells.
`Release of gastrin is under regulation of central neural
`activation, local distension, and chemical composition
`of gastric content. Gastrin stimulates parietal cells by
`binding with gastrin receptors. Gastrin also exerts its ac-
`tion in an indirect manner by causing the release of
`histamine from ECL cells.1 Binding to respective
`G-protein coupled receptors by Ach, gastrin, and hista-
`mine results in activation of second-messenger systems.2
`Vagal stimulation and the action of gastrin (from duo-
`denal and antral G cells) stimulate release of histamine
`from paracrine-ECL cells or mast cells. Increased levels
`of both intracellular Ca2+ by gastrin/Ach and cyclic
`AMP by histamine finally cause acid secretion.13 The
`final step in acid secretion is mediated by H+/K+-ATP-
`ase, also called as gastric proton pump.14 Activation
`of either the cAMP or Ca2+-dependent pathway or both
`causes stimulation of H+/K+-ATPase on parietal cells15
`(Fig. 1).
`
`Figure 1. Mechanism of gastric acid secretion.16
`
`1.2. Disorders associated with elevated secretion of gastric
`acid
`
`(a) Peptic ulcers: Neuropeptide Y, corticotrophin-re-
`leasing factor, bombesin, calcitonin, neurotensin,
`interlukin 1, along with somatostatin, prostaglan-
`dins, bicarbonates, and mucin act as mucosal
`defense factors. Imbalance between these mucosal
`defense factors and aggressive factors (acid and
`pepsin) is involved in peptic ulcers2 (Fig. 2). Their
`rational treatment is aimed at restoring this bal-
`ance. In case of duodenal ulcers (DU), there is
`increase in basal acid secretion. In gastric ulcers
`(GU), however, there is weakening of mucosal
`defenses that can lead to injury in spite of low acid
`secretion. Differences between DU and GU are
`summarized in Table 2. H. pylori and non-steroidal
`anti-inflammatory drugs (NSAIDs) play important
`role in ulcer induction.1 Particularly NSAIDs inhib-
`it production of prostaglandins from arachidonic
`acid by inhibiting enzyme cyclooxygenase (COX).
`Chronic NSAID users are at 2–4% risk of develop-
`ing a symptomatic ulcer, gastrointestinal bleeding
`or associated perforation. In ulcer patients, NSA-
`IDs increase the risk of probable complications
`fourfold. Further, these complications may remain
`undetected because of reduction in pain, thereby
`worsening the condition. Co-administration of Mis-
`oprsotol, the synthetic prostaglandin analog or acid
`suppression therapy may be beneficial. Proton
`pump inhibitors are superior to H2-receptor antag-
`onist in promoting healing and preventing recur-
`rence of both GU and DU1 (see Fig. 3).
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 3 of 25
`
`

`

`1184
`
`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`
`Protective:
`Prostaglandins
`
`Mucus
`
`Bicarbonate
`Somatostatin
`
`
`Aggressive:
`Acid
`Pepsin
`NSAIDs
`Helicobacter Pylori
`
`Figure 2. Factors involved in maintaining acid balance.
`
`(b) Zollinger–Ellison (Z-E) syndrome: In this disease, a
`non-b cell tumor of the pancreatic islets may pro-
`duce gastrin in a quantity sufficient to stimulate
`the secretion of gastric acid to life-threatening lev-
`els. This can lead to severe gastroduodenal ulcer-
`ations and other consequences of the uncontrolled
`hyerchlorhydria. The therapy is aimed at reducing
`gastric acid secretion. In this the proton pump
`inhibitors being surely the drugs of choice.2 ECL-
`cells carcinoids are rare events that have been
`described in association with Z-E syndrome.19
`(c) Helicobacter pylori (H. pylori) infection: Around
`40% of patients over 40 years age and with peptic
`ulcer disease are infected with H. pylori infection.
`H. pylori is a gram-negative rod-shaped bacteria
`and has clearly been associated with gastritis, peptic
`ulcers, gastric adenocarcinoma, and gastric b-cell
`lymphoma. Up to 80–90% of ulcers may be associ-
`ated with H. pylori infection of stomach. This infec-
`tion may
`lead to impaired production of
`somatostatin by D cells. This results into increased
`gastric acid secretion along with impaired duodenal
`bicarbonate production.1 H. pylori infection is now
`
`proven to be a risk factor for gastric cancer and the
`organism was classified as group-I carcinogen by
`WHO.20 H. pylori infection also causes inflamma-
`tion of the antral gastric mucosa. Bacterial prod-
`ucts and inflammatory cytokines may produce
`changes in the endocrine function.21 It has now
`became a standard care procedure to eradicate the
`infection in patients with gastric and duodenal
`ulcers. This strategy is almost successful in eliminat-
`ing the risk of ulcer recurrence (Fig. 4).1
`(d) Gastro esophageal reflux disease (GERD): It is a
`disorder of defense mechanism at the esophageal
`junction, caused by regurgitation of the gastric con-
`tents, especially of gastric acid. GERD is associated
`with decreased gastric emptying and/or increased
`incidence of transient lower esophageal relaxation
`(T-LESR).23 Smoking and obesity increase the
`incidence of GERD symptoms like heartburn, belch-
`ing, and bloating. GERD is not life-threatening, but
`can cause significant discomfort and increased risk
`esophagus.2 Relationship between
`of Barrett’s
`GERD symptoms and incidence of esophageal ade-
`nocarcinoma has also been suggested. It has also
`been linked to tracheopulmonary symptoms like lar-
`yngitis and asthma. Besides disturbed gastrointesti-
`nal motility,
`injurious effects of
`the acid-peptic
`refluxate on the esophageal epithelium are also
`responsible for GERD symptoms. Hence along with
`prokinetic drugs, suppression of gastric acid is the
`current pharmacotherapeutic approach for its treat-
`ment.1 H. pylori infection does not necessarily corre-
`late with GERD, although a reduction in acid
`secretion reduces chances of reflux.23
`
`Table 2. Distinguishing features of the two major forms of peptic ulcers18
`
`Serial No.
`
`Features
`
`Duodenal ulcer
`
`Gastric ulcer
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Incidence
`
`Etiology
`
`Pathogenesis
`
`Pathological
`changes
`
`Complications
`
`Clinical features
`
`Less common than duodenal ulcers
`Usually beyond 6th decade
`More common in males than in females (3.5:1)
`Gastric colonization with H. pylori asymptomatic
`but higher chances of development of duodenal
`ulcers. Disruption of mucus barrier most
`important factor. Association with gastritis, bile
`reflux, drugs, alcohol, and tobacco
`
`Four times common than gastric ulcers
`Usual age 25–50 years
`More common in males than in females (4:1)
`Most commonly as a result of Helicobacter pylori
`infection
`Other factors are hypersecretion of acid-pepsin,
`association with alcoholic cirrhosis, tobacco,
`hyperparathyroidism, chronic pancreatitis, blood
`group O, genetic factors, etc.
`Usually normal-to-low acid levels: hyperacidity if
`Mucosal digestion from hyperacidity most
`present is due to high serum gastrin
`significant factor
`Protective gastric mucus barrier may be damaged Damage to mucus barrier is a significant factor
`Most common in the first part of duodenum
`Most common along the lesser curvature and
`pyloric antrum
`Grossly similar to duodenal ulcers
`
`Often solitary, 1–2.5 cm in size, round to oval,
`punched out
`Commonly hemorrhage, perforation, sometimes
`obstruction, are observed. However, malignant
`transformation never occurs
`Pain food relief pattern
`Night pain common
`No vomiting
`Melaena more common than hematemsis
`No loss of weight
`No particular choice of diet
`
`Perforation, hemorrhage and at times obstruction,
`are common. Malignant transformation less than
`1% cases
`Food pain pattern
`No night pain
`Vomiting common
`Hematemsis more common
`Significant loss of weight
`Patients choose bland diet devoid of fried food,
`curries etc.
`No seasonal variation
`Marked seasonal variation
`Occurs more commonly in people at greater stress More often in laboring groups
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 4 of 25
`
`

`

`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`1185
`
`Figure 3. Peptic ulcer.17
`
`Figure 4. Helicobacter pylori.22
`
`(e) Stress–related ulcers: These are the ulcers of stom-
`ach and duodenum that usually occur as a result
`of severe systemic or CNS illness or trauma. Both
`acid and mucosal ischemia are involved in the etiol-
`ogy of stress ulcers. Similarly, stress due to physio-
`logical factors like septicemia, intracranial lesions,
`alcohol intake, and smoking can also appreciably
`contribute to ulcer induction. Intravenous H2-re-
`ceptor antagonist and intravenous PPIs are pre-
`ferred agents for its treatment.1
`(f) Non-ulcer dyspepsia: It refers to ulcer-like symp-
`toms in patients who are without overt gastroduo-
`denal ulceration. Though pathogenesis of
`this
`syndrome remains unclear, it may occur because
`of gastritis or use of NSAIDs. Empirical treatment
`with acid-suppressive agents is used routinely.1
`
`1.3. Complications arising from the disorders associated
`with elevated secretion of gastric acid18
`
`1.3.1. Obstruction. Development of fibrous scar at or
`near the pylorus results in pyloric stenosis.
`
`1.3.2. Hemorrhage. Minor bleeding by erosion of small
`blood vessels in the base of an ulcer occurs in all the
`
`ulcers and can be detected by testing the stool for occult
`blood.
`
`1.3.3. Malignant transformation. The dictum ‘cancers
`ulcerate but ulcers rarely cancerate’ holds true for most
`peptic ulcers. A chronic duodenal ulcer never turns
`malignant, while less than 1% of chronic gastric ulcers
`may transform into carcinoma.
`
`1.3.4. Perforation. Perforation occurs more commonly
`in chronic duodenal ulcers than chronic gastric ulcers.
`Following sequel may result.
`
`(i) On perforation the contents escape into the lesser
`sac or into the peritoneal cavity, causing acute
`peritonitis.
`(ii) Air escapes from the stomach and lies between the
`liver and the diaphragm giving the characteristic
`radiological appearance of air under the diaphragm.
`(iii) Perforation may extend further to involve adjacent
`organs (liver and pancreas).
`
`2. Therapeutic strategies
`
`Acid secretion is a physiologically important process of
`the stomach as:
`
`1. Acid induces pepsinogen activation to initiate diges-
`tive process and
`2. It kills bacteria and other microbes ensuring a stable
`intragastric environment. However, under certain cir-
`cumstances secretion of large excess of gastric acid
`and pepsinogen injures the gastroduodenal mucosa
`and causes serious and fatal ulcerations.15 Hence, there
`is a need of good gastric acid secretion inhibitors.
`
`The secretion of gastric acid occurs at the level of pari-
`etal cells of oxyntic glands in the gastric mucosa, pro-
`ducing 2–3 L of gastric juice per day (HCl of pH 1).24
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 5 of 25
`
`

`

`1186
`
`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`Based on the understanding of the mechanisms contrib-
`uting to ulcer development and particularly to gastric
`acid secretion, a variety of therapeutic strategies exist.
`These include suppressing the aggressive factors with
`use of antacids, specific antagonists of muscarinic –M1
`receptors, gastrin receptors, histamine-H2 receptors,
`proton pump inhibitors (PPIs), eradication of H. pylori,
`and agonists of prostaglandins/somatostatin recep-
`tors.1,15 These overall strategies are discussed below in
`terms of specific therapeutic agents.
`
`2.1. Antacids
`
`Naturally occurring carbonates, potash, bismuth were
`used as antacids more than century ago. Since then, they
`have been developed and are widely used.25 Antacids are
`compared quantitatively in terms of their acid neutraliz-
`ing capacity. This is defined as the quantity of 1 N HCl
`(expressed in milli equivalents), that can be brought to
`pH 3.5 in 15 min. Antacids neutralize HCl to form water
`and carbon dioxide. Hydroxides of aluminum and mag-
`nesium are the most common constituents of antacid
`preparations. Sodium bicarbonate, calcium carbonate
`are also used, as are other carbonates, silicates, and phos-
`phates. Some antacid preparations combine Al(OH)3 and
`NaHCO3 to achieve both, the rapid effect of carbonate
`and sustained effect of Al(OH)3. Simethicone, a surfac-
`tant that may decrease foaming and thus, esophageal
`reflex, is also included in many antacid preparations.
`Common side effects include alkalosis, belching, nausea,
`abdominal
`distension,
`flatulence,
`diarrhea,
`and
`constipation.1
`
`2.2. Muscarinic antagonists
`
`The secretion of acid, mucus, and pepsinogen in the gas-
`tric mucosa is stimulated via muscarinic receptors. Over-
`expression of M3 receptors in DU patients is proved by
`autoradiographic techniques. Thus, blockade of this
`receptor subtype can reduce the pain by decreasing the
`duodenal motility and provide an effective anti-secretory
`therapy.26 Based on its high affinity to block the musca-
`rinic receptors on the intramural ganglia of stomach
`wall, pirenzepine 1 was developed as an anti-secretory
`drug, which was followed by telenzepine 2, a more po-
`tent derivative with improved healing rates.27 Parasym-
`pathetic side effects of these agents include dry mouth,
`blurred vision, and constipation. These side effects along
`with their incomplete inhibition of gastric acid secretion
`limit their clinical utility28 (see Fig. 5).
`
`2.3. H2 receptor antagonists
`
`H2 receptor antagonists completely inhibit the interac-
`tion of histamine 3 with H2 receptors, thereby reducing
`both volume and H+ ion concentration of the gastric
`juice. They are selective and have little or no effect on
`H1 receptors. They also inhibit acid secretion elicited
`by gastrin, muscarinic agonists, food, sham feeding, fun-
`dic distension, as well as other pharmacological agents.
`They also inhibit basal and nocturnal acid secretion.
`This effect contributes in a major way to their clinical
`efficacy.1
`
`Black et al.,5 identified H2-receptor and prototype H2-
`receptor antagonist, burimamide 4. The potency of
`burimamide at
`inhibiting gastric acid secretion far
`exceeded anticholinergic drugs and was devoid of side
`effects. However, it had poor bioavailability. It was sub-
`sequently replaced by metiamide 5, which also because
`of its side effects like agranulocytosis was withdrawn
`from the clinical trials.29,30 Cimetidine7 6 was the third
`H2 receptor antagonist to be tested in humans and was
`similar to metiamide in its pharmacological profile, but
`did not cause agranulocytosis. Discovery of this mole-
`cule reduced the necessity of surgical procedures for
`peptic acid diseases. Further, ranitidine8 7 was intro-
`duced as more potent drug in 1981 with a much superior
`safety profile.2 Third and most potent antagonist was
`Famotidine31 8 available for clinical use, being 20–50
`times more potent than cimetidine and 6–10 times more
`potent than ranitidine.32 nizatidine33 9 and roxatidine34
`10 followed famotidine. Each of these drugs are rapidly
`absorbed and eliminated after oral administration.35 H2
`receptor antagonists are histamine congeners that con-
`tain a bulky cysteamine side chain in place of ethylamine
`moiety of histamine. Earlier representatives of these
`groups such as burimamide, metiamide, and cimetidine
`retained the imidazole ring of histamine. This ring was
`further replaced by furan in ranitidine, by thiazole in
`famotidine nizatidine, and by piperidylbenzyloy as in
`roxatidine.1 This helped to avoid unwanted cytochrome
`P450 interactions36 (Fig. 6).
`
`H2 receptor antagonists are generally extremely safe
`drugs with incidence of adverse effect of cimetidine less
`than 3%. Adverse effects include dizziness, nausea,
`skin-rashes, somnolence, confusion, impotence, gyneco-
`mastia, hematological effects, and altered function of
`immune system. Rarely they may cause bone marrow
`depression, hepatitis, and anaphylaxis.1 Cimetidine
`
`O
`
`N
`
`N
`
`N CH3
`
`S
`
`CH3
`O
`
`O
`
`N
`
`N
`
`NH
`
`O
`
`NH
`
`NH
`
`Figure 5. Structures of muscarinic antagonists.
`
`Pirenzepine 1
`
`Telenzepine 2
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 6 of 25
`
`

`

`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`1187
`
`S
`
`CH3
`
`NH
`
`NH
`
`Burimamide 4
`
`NH
`
`N
`
`CN
`
`N
`
`NHCH3
`
`NH
`
`CH3
`
`S
`
`Cimetidine 6
`
`NO2
`
`NHCH3
`
`NH
`
`N
`
`NH
`
`S
`
`Ranitidine 7
`
`S
`
`NH2
`
`Famotidine 8
`
`N
`
`SO2NH2
`
`NO2
`
`NHCH3
`
`CH3
`
`O
`
`O
`
`NH
`
`NH
`
`S
`
`Nizatidine 9
`
`O
`
`Roxatidine 10
`
`NH2
`
`S
`
`NHCH3
`
`NH
`
`NH
`
`N
`
`Histamine 3
`
`CH3
`
`S
`
`Metiamide 5
`
`N
`
`NH
`
`CH3
`
`NCH3
`
`O
`
`NH2
`
`NH2
`
`N
`
`S
`
`N
`
`S N
`
`CH3
`NCH3
`
`N
`
`Figure 6. Structures of H2-receptor antagonists.
`
`selectively showed anti-androgen properties in a small
`number of patients.37
`
`tions of this triple therapy include complex regimen
`and related nausea, diarrhea, and dizziness.1
`
`2.4. Eradication of H. pylori infections
`
`2.5. Other agents used
`
`Helicobacter pylori is a gram-negative rod-shaped bacilli
`that colonizes in the mucus on the luminal surface of
`gastric epithelium. H. pylori infection causes inflamma-
`tory gastritis and is a putative contributor to peptic ulcer
`disease, gastric lymphoma, and adenocarcinoma.1
`
`Infection may not always be causative as ulcers may re-
`cur in patients who have undergone successful eradica-
`tion treatment.38 Double or
`triple
`antimicrobial
`therapies, in combination with antisecretory drugs, are
`being used successfully to treat peptic ulcers. Bismuth
`compounds are also been included in regimen probably
`due to their cytoprotective action. Triple therapy with
`metronidazole, a bismuth compound and either tetracy-
`cline or amoxycillin for two weeks is recommended to
`treat H. pylori infections. However, therapeutic limita-
`
`Carbenoxolone 11, an olendane derivative of glyc-
`yrrhizic acid, a compound found naturally in licorice,
`is also useful in the treatment of peptic ulcer. Mecha-
`nism of action is not clear, but appears to alter the com-
`position and quantity of mucus. It is not approved for
`use in U.S., but is being used in Europe since 1962 for
`the treatment of peptic ulcer. Being a steroid analog, it
`exhibits
`substantial mineralocorticoid activity like
`hypertension, hypokalemia, fluid retention, etc.1
`
`Sucralfated polysaccharides inhibit pepsin mediated
`protein hydrolysis. The octasulfate of sucrose was ob-
`served to inhibit peptic hydrolysis in vitro. Reaction of
`sucrose octasulfate with AI(OH)3 forms a viscous sub-
`stance, sucralfate 12. A variety of mechanisms have been
`proposed to account for the cytoprotective and healing
`
`Patent Owners' Ex. 2048
`IPR2018-00272
`Page 7 of 25
`
`

`

`1188
`
`K. S. Jain et al. / Bioorg. Med. Chem. 15 (2007) 1181–1205
`
`effects of sucralfate, including stimulation of prostaglan-
`din synthesis, absorption of pepsin, and stimulation of
`local production of epidermal growth factor.39
`
`Prostaglandins PGE2 13 and PGI2 14 are synthesized by
`gastric mucosa and stimulate the secretion of mucus and
`bicarbonate. Because the administration of prostaglan-
`dins protects the gastric mucosa of animals against var-
`ious ulcerogenic insults, a number of slowly metabolized
`prostaglandin analogs have been developed and tested
`in human beings. Example includes misoprostol 15,
`which is currently approved for prevention of gastric ul-
`cers. Side effects of misoprostol
`include diarrhea,
`abdominal
`cramps, and abortifacient
`in pregnant
`women40 (Fig. 7).
`
`2.6. The proton pump inhibitors (PPIs)
`
`Proton pump is the ultimate mediator of gastric acid
`secretion by parietal cells. With the identification of
`H+/K+-ATPase as the primary gastric proton pump, it
`was proposed that activation of H+ secretion occurred
`by incorporation of H+/K+-ATPase-rich tubulovesicles
`into the apical plasma membrane and that the pumps
`were re-sequestered back into the cytoplasmic compart-
`ment on return to the resting state.41 Inhibition of the
`protons pumping H+/K+-ATPase as a means of control-
`ling gastric pH has attracted considerable attention in
`recent years with the discovery of benzimidazole sulfox-
`ide class of anti-secretory agents. Ruwart et al.42 identi-
`fied timoprazole 16 as one of the first well-