New drugs to suppress acid secretion: current and future developments

THERAPEUTICSTRATEGIES

DRUG DISCOVERY

TODAY

New drugs to suppress acid secretion:current and future developmentsCarmelo ScarpignatoLaboratory of Clinical Pharmacology, Department of Anatomy, Pharmacology & Forensic Sciences, School of Medicine & Dentistry, University of Parma, Italy

Drug Discovery Today: Therapeutic Strategies Vol. 4, No. 3 2007

Editors-in-Chief

Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK

Eliot Ohlstein – GlaxoSmithKline, USA

Gastrointestinal diseases

Despite the dramatic success of pharmacological acid

suppression in healing peptic ulcers and managing

patients with gastro-oesophageal reflux disease

(GERD), a number of challenges remain in the manage-

ment of acid-related disorders. Some new drugs are

currently being investigated to provide a significant

advance on current treatments. Some of them (namely

new drug formulations, novel proton pump inhibitors

(PPIs), potassium-competitive acid blockers (P-CABs),

and CCK2-receptor antagonists) have already reached

clinical testing while some others (like H3-receptor

ligands or NO-releasing antisecretory compounds)

are still in preclinical development and need the proof

of concept in human beings.

E-mail address: C. Scarpignato ([email protected])

1740-6773/$ � 2007 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2007.09.003

Section Editor:Gareth J. Sanger – Immuno-Inflammation Centre ofExcellence for Drug Discovery, GlaxoSmithKline, Stevenage,Hertfordshire, UK

Introduction

The discovery of gastrin by John Edkins initiated the scientific

examination of the regulation of gastric acid secretion and

led to elucidation of the pathogenic basis of peptic ulcer (PU)

and its subsequent cure [1]. During the course of the century

after this breakthrough, the identification of the cellular

regulators of acid secretion culminated in the development

of novel pharmacotherapeutic agents, namely H2-receptor

antagonists (H2-RAs) and proton pump inhibitors (PPIs),

which allowed the effective and safe treatment of PU and

other acid-related disorders [2]. Although antisecretory ther-

apy has advanced dramatically since the introduction of

cimetidine in the mid-1970s, there are several identifiable

unmet needs especially in the management of gastro-oeso-

phageal reflux disease (GERD), where an antisecretory ther-

apy with rapid onset of action and sustained antisecretory

effect would be desirable [3]. This is also true in the manage-

ment and prevention of non-variceal upper GI bleeding and

may be increasingly important in patients taking non-ster-

oidal anti-inflammatory drugs (NSAIDs) [3].

Although with both classes of antisecretory drugs an effec-

tive and rapid healing of the acute disease can be accom-

plished, neither maintenance nor intermittent treatment

with these antisecretory compounds fully prevents PU relapse

[2]. Since Warren and Marshall first described the infectious

aetiology of peptic ulcer disease in 1984, a great deal of

evidence has accumulated to suggest that Helicobacter pylori

eradication therapy cures PU disease and can be beneficial

also to other H. pylori-related diseases [4]. Raising intragastric

pH improves antimicrobial efficacy of chemotherapeutic

agents towards H. pylori through several mechanisms [5], thus

increasing their bactericidal effectiveness. As a consequence,

the combination of a PPI with two antimicrobials (mainly

clarithromycin and amoxicillin or metronidazole) is now a

well-established first-line regimen whenever eradication of

the microorganism is indicated [4,5].

In addition to PU, PPIs are effective for treatment of other

acid-related disorders, including GERD and its complications,

NSAID-associated gastro-duodenal ulcers as well as PU bleed-

ing. In patients with reflux esophagitis the degree of mucosal

healing is directly related to the proportion of time during the

24-hour period for which the intragastric pH is maintained

155

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http://dx.doi.org/10.1016/j.ddstr.2007.09.003

Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases Vol. 4, No. 3 2007

above 4 [6]. As a consequence, numerous studies have docu-

mented the marked efficacy of PPIs (which proved to be

superior to H2-RAs) in controlling symptoms of GERD and

healing esophagitis [6]. There is a strong rationale for PPI use

in both treatment and prevention on NSAID-associated gas-

tro-duodenal ulcers [7] because NSAID-associated mucosal

damage is a pH-dependent phenomenon. Unlike H2 blockers,

PPIs protect from NSAID injury not only the duodenum, but

also the stomach, where the majority of mucosal lesions are

usually located [8].

The goal of medical therapy for bleeding ulcers has been

traditionally to sustain intragastric pH > 6, inorder topromote

platelet aggregation, clot formation and stability. H2-RAs show

little benefit in patients with PU bleeding, which reflects their

inadequate pHcontrol and the rapidonsetof tolerance. Several

meta-analyses (for review see [9]) have shown that treatment

with a PPI reduces the risk of re-bleeding and the requirement

for surgery after ulcer bleeding but has no benefit on overall

mortality, an effect seen only with intravenous administration

of high doses to high-risk patients [9].

PPIs versus H2-RAs: who is the winner?

H2-RAs have a relatively short duration of action and,

depending on the individual agent and whether the patient

is in a fed or fasting state, suppress acid for approximately four

to eight hours. Consequently, multiple daily doses of these

agents are likely to be required. Furthermore, H2-RAs produce

incomplete inhibition of post-prandial gastric acid secretion.

Overall, these agents inhibit acid secretion by up to 70% over

a 24-hour period [2,6].

A further shortcoming is that tolerance to standard H2-RAs

generally develops within two weeks of repeated administra-

tion, resulting in a decline in acid suppression. This can be

explained by a gastrin-induced increase in ECL-derived his-

tamine concentrations at the H2-receptor on the parietal cell

and up-regulation of both gastrin and H2-receptors [6]. By

contrast, PPIs control both basal and food-stimulated acid

secretion and produce more complete and longer lasting acid

suppression than H2 blockers [2]. Such acid inhibition vir-

tually abolishes the damaging peptic activity of gastric juice.

In addition, tolerance to proton pump inhibitors has not

been observed, an advantage presumably attributable to the

fact that they act at the final site of acid production, thereby

blocking the effects of any compensatory mechanisms pro-

moting acid secretion [2]. Physicians generally perceive PPIs

to be more effective than H2-RAs. Consequently, their pre-

scribing has increased sharply each year since their introduc-

tion into the market [10].

Shortcomings of current PPIs and unmet needs in acid

suppression

Although effective and safe, currently available PPIs are still far

from the ideal antisecretory compound. Currently available

156 www.drugdiscoverytoday.com

PPIs have notable limitations [11]. These drugs exhibit sub-

stantial interpatient variability in pharmacokinetics and some

may have clinically significant interactions with other drugs.

The time of dosing and ingestion of meals may also influence

the pharmacokinetics of these agents as well as their ability to

suppress gastric acid secretion. First-generation PPIs (i.e. ome-

prazole, pantoprazole and lansoprazole) have a relatively slow

onset of pharmacological action and may require several doses

to achieve maximum acid suppression and symptom relief,

possibly limiting their usefulness in on-demand GERD ther-

apy. First-generation PPIs may also fail to provide 24-hour

suppression of gastric acid, and nocturnal acid breakthrough

(NAB, defined as a drop of intragastric pH under 4 for more

than one hour) can occur even with twice-daily dosing [11].

There is however increasing evidence of both inappropriate

prescribing and inappropriate use of these drugs. Only seldom,

indeed, primary care physicians give their patients advice on

when and how to take their medication [2].

Despite the dramatic success of pharmacological acid sup-

pression, a number of challenges remain in the management

of acid-related disorders [3]. These include management of

patients with gastro-oesophageal symptoms who do not

respond adequately to PPI therapy, treatment of patients

with non-variceal upper GI bleeding who re-bleed after endo-

scopic haemostasis, prevention of stress-related mucosal

bleeding in the ICU, best treatment and prevention of

NSAID-related GI injury, and optimal combination of anti-

secretory and antibiotic therapy for the eradication of H.

pylori infection [3].

What’s in the current GI pipeline?

Rationalization within the pharmaceutical industry to combat

escalating costs has included the close examination of research

portfolios. Gastroenterology has been one of the casualties of

this exercise and few companies currently retain a specific

gastrointestinal research programme [12].Many of the existing

drugs are in a mature stage of their life cycle and some of the

leading compounds in the GI market have been or are close to

patent expiration. Notwithstanding, the upper GI pipeline is

small with only 33 products across all stages of development.

The majority of them are in phase II with only three drugs in

phase III [13]. AstraZeneca, who discovered the first PPI more

than 20 years ago, synthesized and started the development of

esomeprazole (the magnesium salt of the S-isomer of omepra-

zole) in 1990, making it available for clinical practice world-

wide at the beginning of the third Millennium. Together with

the big players (e.g. AstraZeneca, TAP Pharmaceuticals and

Nycomed), new smaller companies have entered the game and

are developing either novel formulations of currently available

PPIs or novel PPIs [2]. In addition, new avenues (i.e. compe-

titive blockade of proton pump at K+ exchange sites) [14] or

blockade of CCK2 (e.g. gastrin) receptors on the parietal and

ECL cells [15] are being explored.

Vol. 4, No. 3 2007 Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases

Drugs under clinical investigation

In this section, the new PPI formulations currently under

development or recently introduced in clinical practice as

well as the novel acid lowering drugs, which already reached

clinical testing, will be discussed.

New formulations

Extended-release formulations of PPIs will become an increas-

ingly important strategy used by pharmaceutical companies,

as they will be useful for the potential treatment of NAB

because of their controlled and sustained release [2]. This is a

strategy that is being adopted by AGI Therapeutics, who is

developing in cooperation with Axcan Pharma AGI-010, a

delayed and controlled-release (ChroNAB technology) for-

mulation of omeprazole. This is also a strategy that has been

used by TAP Pharmaceuticals for its modified release version

of dexlansoprazole (TAK-390MR) [2]. The preliminary

results of a pharmacokinetic and pharmacodynamic evalua-

tion have just been presented at the Digestive Disease Week

[16]. The study showed that TAK-390MR has an extended

drug exposure compared to the parent compound (i.e. lan-

soprazole). Twenty-four-hour intragastric pH recording also

showed across all dose levels (60, 90 and 120 mg) a prolonged

acid inhibition. Eisai too is developing an extended-release

version of Pariet/Aciphex (rabeprazole) for the treatment of

upper GI disorders, which is however still in Phase I [13].

Currently available PPIs are orally administered as gastro-

protected preparations. The different enteric coatings (gran-

ules encapsulated in a gelatine shell, tablets or multiple unit

pellet system (MUPS)), which are necessary to protect the

acid-labile PPI from acid degradation within the stomach,

have the potential disadvantage of delaying PPI absorption

and, as a consequence, the available PPI formulations are

considered delayed-release (DR) preparations. The recently

FDA-approved immediate-release (IR) omeprazole for-

mulation displays a different pharmacokinetics and pharma-

codynamics compared with the standard, DR preparation

[17]. This formulation (available as sachets, capsules or chew-

able tablets) consists of pure, non-enteric-coated omeprazole

powder (40 or 20 mg per unit dose) along with 1680 mg of

sodium bicarbonate (containing 460 mg of sodium). The

antisecretory effect of IR omeprazole is quicker than that

observed with classical DR formulation while the duration

of the acid lowering activity is similar [17]. The early increase

in intragastric pH is probably because of the neutralizing

capacity of sodium bicarbonate, which also accelerates and

enhances absorption of omeprazole whose increased bioa-

vailability translates into a more profound acid suppression.

Vecta Ltd (an Israeli Company) is currently investigating

Vecam (VB101) for the potential treatment of GERD. Vecam

is a combination of a PPI with a chemical ‘acid pump acti-

vator’ to allow a meal-independent antisecretory effect. In

order to identify compounds that induce acid secretion in

humans, Vecta screened several small molecules that were

known to have acid-promoting properties. VB101 was chosen

because oral administration of the compound in humans

displays the same acid stimulating activity of pentagastrin

(http://www.vecta.co.il/products_vecam.html).

Novel PPIs

Several new PPIs have been synthesized since the discovery of

omeprazole. The majority of them is still in preclinical devel-

opment or have been abandoned [2]. Ilaprazole (compound

marked IY-81149, Fig. 1) is a benzimidazole compound

synthesized at Il-Yang (South Korea) and presently developed

by TAP Pharmaceuticals. Its antisecretory activity proved to

be two to three times higher and its half-life two to three

times longer than that of omeprazole. Although the drug is

already on the market in South Korea, a phase II clinical trials

is ongoing in USA (http://www.clinicaltrials.gov).

Allergan is developing a pro-drug (AGN 201904), which is

actually the acid-stable sodium salt of a sulfonamide of

omeprazole. This compound was designed to have delayed

absorption in order to prolong the plasma residence time and

thus increase the number of proton pumps within the gastric

secretory canaliculus that might be inhibited. In an ambu-

latory 24-hour intragastric pH recording in healthy, H. pylori-

negative male subjects [18], AGN 201904 was shown to

provide faster and more profound acid suppression than

esomeprazole on days 1 and 5. Nocturnal acid suppression

was also greater by >2 pH units after five days, and the

median pH never dropped below 5.0 with AGN. This medica-

tion may therefore be useful for patients with nocturnal

symptoms or perhaps even for patients who need rapid

and robust acid suppression, such as those with PU-related

bleeding.

Tenatoprazole (compound also marked TU-199) has been

developed by Mitsubishi Pharma in Japan and is now under

active development by Negma-Gild (France). Conversely from

all the other PPIs, this compound is not a benzimidazole

derivative, consisting of one imidazopyridine ring connected

to a pyridine ring by a sulfinylmethyl chain (Fig. 1). It repre-

sents therefore a new chemical entity. The inhibitory activity

of this novel compound on gastric H+,K+-ATPase has been

thoroughly characterized by George Sachs’ Team [19]. Like

the other PPIs, tenatoprazole is a prodrug (pKa = 4.04), which is

converted to the active sulfenamide or sulfenic acid by acid in

the secretory canaliculus of the stimulated parietal cell of the

stomach. This active species binds to luminally accessible

cysteines of the gastric H+,K+-ATPase resulting in disulfide

formation and acid secretion inhibition. The binding sites of

tenatoprazole were at Cys813 and Cys822 as shown by tryptic

and thermolysin digestion of the ATPase labeled by tenato-

prazole. Both of these sites are located in the proton transport

pathway, though cysteine 822 is found deeper in the TM5/6

membrane domain than cysteine 813 (Fig. 2) [19].

www.drugdiscoverytoday.com 157

http://www.vecta.co.il/products_vecam.html

http://www.clinicaltrials.gov/


Figure 1. Chemical structure of ilaprazole (upper panel) and tenatoprazole (lower panel), two novel PPIs, currently under active development. Note that

ilaprazole belongs – like the other PPIs – to benzimidazole compounds whereas tenatoprazole represents a different chemical entity.

Pharmacokinetics studies revealed that tenatoprazole dis-

plays a long half-life (8.7 � 2.6 hours for repeated adminis-

tration of 40 mg) and pharmacodynamic investigations on

the same subjects have shown an increase of intragastric pH

with tenatoprazole 40 mg daily for seven days significantly

higher (p < 0.05) than that observed with the same regimen

of esomeprazole, the median pH being 4.6 � 0.9 and

4.2 � 0.8, respectively [20]. A further investigation [21] did

confirm and extended previous data showing the prolonged

duration of acid suppression with tenatoprazole.

Like the other PPIs, tenatoprazole is a racemic mixture of

two stereoisomers, which derive from the chiral nature of

the sulfur atom of the sulfinyl group. Therefore, in order to

exploit the features of stereoselective catabolism, the S-

isomer was selected for further development. A careful

pharmacokinetic and structural study [19] showed that

the oral bioavailability of S-tenatoprazole sodium salt

hydrate is almost twice that of S-tenatoprazole free form.

The difference in bioavailability can be explained by the

better solubility of the sodium salt because of its peculiar

crystal structure. The crystal form of S-tenatoprazole

sodium salt hydrate is indeed quite different from that of

S-tenatoprazole free form (Fig. 3). In the crystal of S-tena-

toprazole, sodium salt hydrate there is a loose packing

structure of molecules, which results in rapid water access

and hence greater solubility. The pharmacokinetics of

S-tenatoprazole sodium was then studied in healthy volun-


teers and proved to be linear with a dose-related increase in

both Cmax and AUC [Ficheux et al., unpublished observa-

tions]. The results of a dose ranging (30, 60 and 90 mg daily)

pharmacodynamic study have recently been presented [22]

and show that all the doses of S-tenatoprazole Na resulted

in a higher median pH on day 5 compared to esomeprazole

(40 mg daily). The drug provided significant greater and

more prolonged and dose-dependent acid suppression that

the comparator (namely esomeprazole) either during the

day and the night.

All these data clearly show that – compared to the existing

PPIs – tenatoprazole has a longer half-life and a longer dura-

tion of the antisecretory action, in agreement with the cur-

rent knowledge according to which the antisecretory effect is

proportional to the AUC [23]. Although these properties

should theoretically translate into a better therapeutic effi-

cacy, no randomized clinical trials in acid-related diseases are

available as yet. However, the available studies point out both

pharmacokinetic and pharmacodynamic advantages of tena-

toprazole over esomeprazole. It is conceivable that tenato-

prazole could similarly be better than the other existing PPIs

because esomeprazole provides – amongst the members of

the class – the most effective control of intragastric pH

whatever the parameter considered [24]. S-Tenatoprazole

sodium then appears to be a promising PPI for the treatment

of acid-related diseases, where it has the potential to address

unmet clinical needs [25].


Figure 2. Location of the cysteines that are bound covalently by the different PPIs. The sites in the vestibule and in the membrane domain are responsible

for the covalent inhibition of acid transport. The cytoplasmic domain has been removed and only the membrane and exoplasmic domain is shown. The

binding of the PPIs is to the major transport domain of the pump, in particular M5/M6 at cysteine 813 (all PPIs) and cysteine 822 (circled in blue), which is

located deeper in the membrane domain. Lansoprazole also binds a third cysteine (i.e. 892). Courtesy of Professor Irvin Modlin (Yale University, CT, USA).

Figure 3. X-ray powder diffraction spectrum of S-tenatoprazole. Upper panel: crystalline molecular packing of S-tenatoprazole sodium salt hydrate. On

the left, crystal structure; on the right, unit cell of the crystals. Lower panel: crystalline molecular packing of S-tenatoprazole free form. On the left, crystal

structure; on the right, unit cell of the crystals (from Shin et al. [19]).



Potassium-competitive acid blockers

The next generation of drugs that suppress gastric acidity will

most probably be acid pump antagonists, which are K+-com-

petitive inhibitors of the ATPase [14]. Although the PPIs have

a unique mechanism of action based on their chemistry, acid

pump antagonists have a structural specificity for their target,

the K+-binding region of the H+,K+-ATPase. Despite sharing

the same mechanism of action, P-CABs represent a hetero-

geneous class of drugs. Indeed, they belong to four different

chemical classes, namely imidazopyridines, pyrimidines, imi-

dazonaphthyridines and quinolones [14].

P-CABs are lipophilic, weak bases that have high pKa values

and are stable at low pH. This combination of properties

allows them to concentrate in acidic environments. For

example, the concentration of a P-CAB with a pKa of 6.0

would theoretically be expected to be 100,000-fold higher in

the parietal cell canaliculus (pH 1) than in the plasma (pH

7.4). The concentration of P-CABs in the gastric mucosa is

demonstrated by in vitro and in vivo studies with AZD0865 and

revaprazan [14]. On entering an acidic environment, P-CABs

are instantly protonated and it is in this form that it is

thought to bind to and inhibit the enzyme. This indicates

that these agents will produce more rapid acid inhibition and

will be able to elevate gastric pH to a higher level than PPIs.

Animal studies have shown a close correlation between

maximum inhibition of acid output and the logarithm of

Cmax [14], thus suggesting that the duration of action of P-

CABs will depend on their half-life. The main differences

between P-CABs and PPIs are summarized in Table 1. It is

evident that P-CABs offer a more rapid elevation in intragas-

tric pH than a PPI (and similar to that achieved by an H2-RA)

while maintaining the same degree of antisecretory action,

whose duration is dependent on half-life and can easily be

prolonged by extended release formulations. Whether these

favorable pharmacodynamic properties will translate into

clinical benefits it is unknown. Despite a number of papers

presented at recent GI meetings and two completed clinical

trials in GERD (http://www.clinicaltrials.gov) AZD0865 was

discontinued [2]. The same holds true for CS526. However, a

follow-up compound of soraprazan (whose pharmacological

properties have only recently been described in detail [26]) is

currently under clinical investigation [2].

Table 1. P-CABs and PPIs: main differences in the mechanism

P-CABs

Acts directly on the H+,K+-ATPase enzyme

Super concentrates in parietal cell acid space

(100,000-fold higher than in plasma)

P-CABs binds competitively to the potassium binding

site of H+,K+-ATPase

Duration of effect related to half-life of drug in plasma

Full effect from first dose


New H2-receptor antagonists

Despite all the intrinsic limitations, there is still a place for

H2-RAs in the era of PPIs [27]. A recent survey of the Castell’s

Team [28] did find that the majority of GERD patients report

persistent improvement of night-time symptoms from bed-

time H2-RA use and suggested that possible clinically impor-

tant tolerance does occur in a small number of patients. In

this connection a fast-dissolving oral tablet containing a fixed

dose combination of a PPI and an H2-RA (product marked OX

17) has been developed by Orexo AB (Upsala, Sweden) and

phase II clinical trials with this formulation are presently on

the way in Europe [2,13]. A combination of H2-RA with the

novel PPI tenatoprazole has also been patented [29]. In a

crossover clinical trial [30], the hypothesis that co-adminis-

tration of famotidine (10 mg daily) and omeprazole (20 mg

daily) would lead to a rapid onset of action of acid suppres-

sion without loss of efficacy of the PPI was tested. On day 1

famotidine and omeprazole in combination improved the

duration of and time to reach intragastric pH > 4 compared

to omeprazole alone.

Although the last decade has been dominated by the

growing use of PPIs, several new H2-RAs have been synthe-

sized. Although the majority of them have been discontin-

ued, few molecules reached clinical development and two

(namely ebrotidine and lafutidine) have actually been

marketed. These drugs belong to a new generation of H2-RAs,

which combine the antisecretory effect with a mucosal pro-

tective activity. Ebrotidine, developed by the Ferrer Group in

Spain, was prematurely withdrawn from the market because

of serious hepatotoxicity [2]. The second compound, origin-

ally developed by Fujirebio Inc., is currently marketed by UCB

and Taiho Pharmaceutical in Japan. Conversely from raniti-

dine and famotidine, lafutidine increases both daytime and

nighttime intragastric pH in H. pylori-negative subjects and

conversely from omeprazole (and other PPIs) its efficacy is not

influenced by the CYP2C19 genotype status [2]. A recent

crossover study [31] in healthy volunteers did show that a

single dose (10 mg) of this novel H2-RA is able to increase

intragastric pH more quickly than a single dose (20 mg) of

rabeprazole, the fastest amongst the available PPIs. Both in

fasting conditions and in the postprandial state, the duration

of the antisecretory action was longer than that of the PPI

of action (from Scarpignato et al. [2])

PPIs

Requires transformation to the active form

Concentrate in parietal cell acid space (1000-fold higher than in plasma)

Sulfenamide binds covalently to H+,K+-ATPase

Duration of effect related to half-life of the sulfenamide–enzyme complex

Full effect after repeated doses

http://www.clinicaltrials.gov/


because the drug maintained the pH over a given threshold

for a sustained period of time.

Gastrin (CCK2) antagonists

Gastrin is a major endocrine regulator of gastric acid secretion

and its release stimulates an estimated mean of 90% of

postprandial secretion. This hormonal peptide is produced

by the antral G cells in response to food proteins and their

digestion by-products as well as upon stimulation by gastrin

releasing peptides from postganglionic fibres of the vague

nerve [1,15]. Besides its central role in the regulation of acid

secretion, gastrin also affects GI motility and stimulates

epithelial cell proliferation throughout the GI tract [1,15].

Molecular biology studies have now established that gastrin

receptors are identical to CCK2 receptors [15,26]. These recep-

tor subtypes have been found not only on parietal cells but

also on enterochromaffin-like (ECL) cells, fundic D cells and

the vagus nerve [15,32].

Given the important physiological role of gastrin in the

stimulation of gastric acid secretion, selective CCK2-receptor

antagonists offer a potential approach to regulate acid produc-

tion. At least 12 chemical classes of CCK-receptor antagonists

have been described and several ligands with high affinity for

CCK2 receptors have been identified and characterized by

binding and pharmacodynamic studies [2,15]. However, only

few have been tested in humans for their effect on acid secre-

tion. Amongst them, spiroglumide and its follow-up com-

pound itriglumide (both from Rotta Research Laboratorium)

are the most interesting ones [2,15]. The pharmacodynamics

and pharmacokinetics of itriglumide were studied in humans,

where the compound inhibited gastrin-stimulated acid secre-

tion in a dose-dependent manner. The pharmacokinetics pro-

ved to be linear in the dose range of 30–600 mg and drug was

well tolerated at any dose level [33]. Itriglumide therefore app-

ears to be a promising CCK2 antagonist that deserves further

clinical investigations in acid- and gastrin-related disorders.

Being CCK2 receptors expressed in the regenerative mucosa

adjacent to the ulcer margin, they can mediate the gastrin-

enhanced cell proliferation underlying ulcer healing [15].

Therefore, despite their acid lowering activity, CCK2 antago-

nists might delay mucosal healing. It is unlikely that these

compounds will be used as antiulcer drugs because of this

concern and because the development of tolerance (observed

in humans with the benzodiazepine derivative YF-476 from

Astellas [2]). Similarly, it is difficult to imagine these agents as

an alternative to PPIs in GERD. On the contrary, their use

together with long-term acid suppression would prevent the

consequences of PPI-induced hypergastrinemia (e.g. ECL cell

hyperplasia or gastrin-driven GI malignancies) [2,34].

A look to the future

An increasing body of evidence suggests that H3 receptors,

which are located in both the CNS and the stomach, are

involved in the regulation of acid secretion as well as mucosal

protection (for review see [15,35]) and several potent and

selective H3-receptor agonists and antagonists have been

synthesized. The activation of H3 receptors by peripheral

administration of the selective agonist (R)a-methylhistamine

reduced acid secretion in several animal species. The anti-

secretory effects were observed against indirect stimuli that

act on vagal pathways or on enterochromaffin-like (ECL)

cells, such as 2-deoxy-D-glucose, food or pentagastrin, but

not against histamine or dimaprit (a selective H2-receptor

agonist). A location of H3 receptors in paracrine cells of the

gastric mucosa rather than in gastrin producing cells or

parietal cells seems more likely because the inhibition was

mainly evident against stimuli, which involve the release of

histamine.

The poor availability of (R)a-methylhistamine limited its

clinical use and led to development of azomethine pro-drugs.

One such pro-drug, BP2-94 (Laboratoire Bioproject),

achieved much higher plasma levels than the parent com-

pound after oral administration in man [35] but the anti-

secretory effect of this compound in man has not been

reported. Although it seems unlikely that this class of drugs

will be more effective than PPIs, the lack of expression of H3

receptors in the human GI tract [36] raises doubts on the

clinical perspective of this approach.

Nitric oxide (NO) is now recognized as a crucial mediator of

GI mucosal defence, exerting many of the same actions as PGs

in the GI tract [37]. For instance, PGs and NO are both capable

of modulating mucosal blood flow, mucus release, and repair

of mucosal injury. Both mediators are also capable of inhibit-

ing neutrophil adherence and activation and mast cell degra-

nulation. In experimental models of gastric injury, NO is

capable of exerting cytoprotective effects similar to those

observed with PGs [37]. As a consequence, much attention

has recently been focused on NO-donating antisecretory

compounds, which should also possess a mucosal protective

activity. The different NO-releasing moieties (nitroxybutyl,

furoxan or nitrosothiol groups) added through a chemical

spacer to conventional antisecretory drugs result in different

physico-chemical properties and different NO-releasing capa-

cities of the hybrid molecules. As organic nitrates, NO-H2-RAs

and NO-PPIs require metabolic degradation by tissue

enzymes (mainly esterases of the intestinal wall and liver)

to release NO, but the rate of NO release is much slower in

comparison with other NO donors. The NO-enhanced H2-RA

NMI-672 and NO-enhanced PPI NMI-826 (both synthesized

by NitroMed via the use of the so-called NitRx technology)

were significantly more efficacious than their respective par-

ent molecules cimetidine and lansoprazole in healing acid-

induced gastric ulcers in rats. Over a seven-day period, NMI-

826 healed 90% of gastric ulcers versus a corresponding 50%

for the parent molecule, lansoprazole [38]. Similar results

have more recently been reported in Italy with furoxan-



derived H2-RAs (namely lamtidine derivative) and PPIs

(namely rabeprazole-related compounds) [39,40].

Conclusions

A number of new drugs are currently being investigated to

provide a significant advance on current treatments. Some of

them (namely P-CABs and CCK2-receptor antagonists) have

already reached clinical testing while some other (H3-recep-

tor ligands and NO-donating antisecretory drugs) are still in

preclinical development and need the proof of concept in

human beings.

Although H2-receptor antagonists (especially soluble or

OTC formulations) will become the ‘antacids of the third

millennium’ and will be particularly useful for on-demand

symptom relief, clinicians will continue to rely on PPIs to

control acid secretion in GERD and other acid-related dis-

eases. In this connection, new formulations, novel com-

pounds and better acid suppressing regimens are welcome.

In gastroenterology, as in other medical specialties, new

potential therapies, both pharmaceutical and invasive, con-

tinually appear on the horizon, always with great initial

enthusiasm. Over time, these either will prove to be failures

or will find their appropriate level of use in our therapeutic

armamentarium. When faced with promising new therapies,

we should always wonder whether they are effective and safe

and whether they are really better than the current ones.

Although acid suppression therapy has stood the test of time,

the new targets for pharmacological manipulation of gastric

secretion will likely bring us a step forward.

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New drugs to suppress acid secretion: current and future developments