Prazoles

Since a substituted benzimidazole was first reported to inhibit the H,K-ATPase by covalent binding [ 1 ], many PPIs have been synthesized and are in clinical use. These all have a similar core structure, 2-pyridy lmethylsulfinyl benzimidazole moiety except tenatoprazole. Tenato-prazole has 2-pyridylmethylsulfinyl pyridoimidazole moiety. 

The anti-ulcer agents omeprazole, lanzoprazole, and pantoprazole have been introduced during the past decade for the treatment of peptic ulcers. Gastric acid secretion is efficiently reduced by prazole inhibition of H+K+-ATPase in the parietal cells of the gastrointestinal mucosa [75]. The prazoles themselves are not active inhibitors of the enzyme, but are transformed to cyclic sulfenamides in the intracellular acidic compartment of parietal cells [76]. The active inhibitors are permanent cations at pH < 4, with limited possibilities of leaving the parietal cells, and thus are retained and activated at the site of action. In the neutral body compartments the prazoles are stable, and only trace amounts are converted to the active drugs. (For a review on omeprazole, see Ref. [77].)... 

Ari pi prazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can be needed for some patients with recurrent mania or mixed states, but the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

The synthesis of sulfoxides from sulfides has been widely explored, and numerous oxidants have been investigated to achieve an efficient and selective sulfoxidation [38]. However, most of the reagents require carefully controlled conditions, including the quantity of oxidants, to avoid the formation of sulfone side products. Control to avoid formation of sulfones is particularly difficult since the first oxidation to sulfoxides requires relatively high energy [38]. m-Chloroperbenzoic acid (mCPBA) has been intensively used in the synthesis of prazole derivatives [39]. 

Proton pump inhibitors -prazole Omeprazole, lansoprazole Gastric ulcers (27)... 

Rezk et al. [74] developed and validated a reversed-phase HPLC assay method for the simultaneous quantitative determination of omeprazole and its three metabolites in human plasma. The method provides excellent chromatographic resolution and peak shape for the four components and the internal standard within a 17-min run time. The simple extraction method results in a clean baseline and relatively high extraction efficiency. The method was validated over the range of 2-2000 ng/ml. The resolution and analysis for the four analytes omeprazole, hydroxyome-prazole, omeprazole sulfone, and omeprazole sulfide and the internal standard utilized a Zorbax C18 (15 cm x 3 mm, 5 /im) with a Zorbax C18 (12.5 cm x 4.6 mm) guard column. The mobile phase consisted of two components. Mobile phase A was 22 mM phosphate monobasic, adjusted to a pH of 6 with diluted sodium hydroxide. This solution was filtered through a 0.45-/im membrane filter, then mixed as 900 ml buffer to 100 ml methanol. Mobile phase B was composed of 100 ml of the phosphate buffer as mobile phase A, mixed with 800 ml of acetonitrile, 100 ml of methanol, and 100 /A of trifluoroacetic acid with an initial flow-rate of 0.55 ml/min and detection at 302 nm. 

In early 1981, Byk Gulden decided gradually to redirect more of the research resources away from anti-muscarinics programme [22,23] to PPIs. At this time, picoprazole became the new state of the art (Fig. 3.5) [24,25]. Some data on pico-prazole had been published previously in Nature [26]. Furthermore, in spring 1981 Byk Gulden became aware of Hassle s patent EP 5129, which focused on the pyridine part of the timoprazole skeleton [27]. 

The PPIs are metabolized to inactive metabolites [5]. Omeprazole s dominant metabolite, 5-hydroxyome-prazole is formed via CYP2C19 metaboUsm, but there is also a minor component metabolized via CYP3A4 forming an omeprazole sulphone. Both are subsequently metabolized to omeprazole hydroxysulphone. 

The IR spectra of 02 adducts of Rh(Q)(PR3)2, Rh(Q)(dppp), where HQ = 1-phenyl-3-methyl-4-R-prazol-5-one, R = 2-thenoyl, 2-furanoyl, show vOO of r 2-peroxo near 890 cm-1.340... 

Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, panto-prazole, and rabeprazole in the treatment of acid-related disorders. J Am Pharm Assoc 2000 40 52-62. 

Omeprazole and related -prazoles are irreversible, direct inhibitors of the proton pump (K+/H+ antiporter) in the gastric parietal cell (see Figure VI-1 -1). 

Omeprazole and the other prazole" proton-pump inhibitors are more powerful inhibitors of gastric i secretion than the antagonists. Their clinical uses and adverse reactions are considered. 

Omeprazole and related -prazoles are irreversible, direct inhibitors of the proton... 

Omeprazole and other members of the prazole family irreversibly inhibit the proton pump. The answer is (D). 

J Nazor, J., Smith, D., and Song, S. (2011) Synthesis of prazole compounds. International Publication Number WO2011/071982 A2, filed Dec. 8, 2010 and issued June 16, 2011. 

De Mey C, Meineke I, Steinijans VW, Huber R, Hartmann M, Bliesalh H, Wurst W. Panto-prazole lacks interaction with antipyrine in man, either by inhibition or induction. IntJ Clin Pharmacol Ther 99A) 32, 98-106. 

A study in epileptic patients found that omeprazole 20 mg daily did not affect the serum levels of phenytoin, whereas earlier studies in healthy subjects su ested that phenytoin levels might be modestly raised by omeprazole 40 mg daily. A study with esome-prazole also suggests it may cause a minor rise in phenytoin levels. Lansoprazole does not normally affect phenytoin levels, but an isolated case report of toxicity is tentatively attributed to an interaction. Pantoprazole and rabeprazole appear not to interact. 

Clarithromycin approximately doubles the serum levels of esomeprazole, lansoprazole and omeprazole, but has no effect on panto-prazole. A small rise in the serum levels of clarithromycin might also occur, which may be therapeutically useful. Some very limited evidence indicates that erythromycin raises serum omeprazole... 

Middle MV, Muller FO, Schall R, Hundt HKL, Mogibucka EM, Beneke PC. Effect of panto-prazole on ovulation suppression by a low-dose hormonal contraceptive. Clin Drug Invest (1995) 9,54-6. 

Two very different approaches to inhibition of the H, K -ATPase exist today. By far the most well documented class of compounds is that of the substituted pyxidinemethylsulphinylbenzimidazoles. These compounds covalently inhibit H, K -ATPase, which means that the pump is inhibited in an irreversible manner. Omeprazole, pantoprazole, lansoprazole, rabe-prazole and others (see Fig. 1) belong to this class of agents. 

The stoichiometry of binding has been investigated in a number of experimental settings. From in vivo labeling of the H, K -ATPase with H-ome-prazole, it was found that approximately 2 mol of radiolabel were bound per mole of active site. The active site concentration was estimated by phosphorylation from P-ATP in the absence of potassium ions. Under those conditions, dephosphorylation is very slow, and the level of P labeling can be used as a measure of the active-site concentration of the H, K -ATPase[15, 17, 18,20]. 

References will mainly be made to omeprazole, the first and most widely documented PPI developed and used in the clinic. In most cases findings have been described and confirmed in studies with lanzoprazole and panto-prazole. Notes about the corresponding findings can be found in prescribing information and investigators brochures for these products, but there are few publications in the literature. 

---