Xvp

Rabeprazole

F2HCO

Esomeprazole Tenatoprazole Ilaprazole

Figure 3 Various PPIs either on the market or in development. Esomeprazole is the (S) enantiomer of omeprazole, and all the other compounds are racemates. Different substitutions on the benzimidazole portion alter the pKa of the benzimidazole nitrogen atom, resulting in different acid liability profiles.

improve stability. By 1975, Hassle was focusing more on acid secretion, and had available to them, in addition to rats and dogs, the rabbit gastric gland model. They then discovered that timoprazole, in contrast to H2 receptor antagonists, inhibited acid secretion in vivo and in vitro, irrespective of the stimulus. Clearly this compound was not an H2 receptor antagonist. Timoprazole was toxic to rats, causing thyroid enlargement and thymic degeneration. Modification of timoprazole to picoprazole resulted in decreased toxicity.

As a polyclonal antibody generated against the enzyme H + /K+-ATPase reacted by radial immunodiffusion with proteins of the thyroid and thymus, it appeared likely that these compounds inhibited the gastric H + /K+-ATPase. When tested against the ATPase in the absence of acid transport, no effect was found. However, as these compounds were acid-labile, further testing showed that timoprazole and picoprazole inhibited both enzyme activity and acid transport in vesicles under acid-transporting conditions. Moreover, there was a lag phase of inhibition when monitoring acid transport,23'24 indicating that the mechanism of action was due to both the weak base properties of the compounds and their being acid-activated prodrugs. With this knowledge, omeprazole was synthesized and launched in 1989 (Figure 2). Subsequently, compounds with the same core structure were also introduced, and two further compounds with a slightly different core structure are under development (Figure 3).

The mechanism of acid activation is quite unique (Figure 4), and has only recently been described.25 Protonation of the pyridine ring with a pKa between 4.0 and 5.0 accounts for the accumulation of the prodrug in the acidic space of the active parietal cell canaliculus (pH e 0.8). Protonation of the benzimidazole nitrogen atom activates the C-2 carbon, allowing reaction with the fraction of the pyridine that is unprotonated, to form a planar tetracyclic cation that is converted to the sulfenic acid and, by dehydration, to the sulfonamide.26 In the presence of the acid-transporting enzyme, the PPIs react with one or more cysteine residues accessible from the luminal surface of the GI tract as the reactive species is a relatively impermeant cation. Omeprazole reacts primarily with Cys813 on the luminal face of the enzyme, and lansoprazole with Cys813 and Cys321, both present in a luminal vestibule, whereas pantoprazole and tenatoprazole react with Cyse813 and Cys822, the latter of which is present in the membrane domain of the enzyme.27

Advances in our understanding of the tertiary structure of the catalytic subunit of the H + /K+- ATPase based on homology modeling of different crystalline forms of the SERCA Ca2 + -ATPase28'29 have allowed the generation of a specific structure of the PPI-bound form of the enzyme. During its transport cycle, the enzyme converts from the basal E1 state to the phosphorylated state with a hydronium ion bound in the ion-binding site in the membrane, and then converts to the E2P form, which then binds K+ with dephosphorylation. This is the form that binds the active form of the PPI. Different conformations of the catalytic subunit of the pump are shown in Figure 5, with the binding sites of pantoprazole on the bottom left.

Knowledge of the mechanism of the PPIs as acid-activated prodrugs allows the prediction of many of their properties. First, since they are covalent inhibitors, their duration of action outlasts their presence in the blood. Since they require acid activation, they are most effective when the parietal cells are stimulated, hence are usually given 30-60 min after meals. Since they generally have a short plasma half-life (60-90 min), and not all acid pumps are active at any one time, their effective is cumulative, reaching a steady state on once-a-day dosing by the third day, inhibiting about 70% of all pumps. Restoration of pump activity depends on de novo synthesis of the pump, which has a half-life of about 54 h, and also on the partial reversal of inhibition by glutathione reduction of the disulfide bond at Cys813.30,31 If there is significant acid secretion at night resulting in night-time GERD, it is difficult to control this with currently available PPIs. Their effect on GERD healing is also superior to their effect on symptom relief. They also heal peptic ulcers and esophageal erosions to greater than 90% within 8 weeks.

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