Structure and SAR of the Proton Pump Inhibitors

In 1973 workers at AB Haessle in Sweden, identified timoprazole (118) as one of the first well-defined inhibitors of the newly discovered gastric proton pump. This compound stemmed from efforts to separate the toxicity and acid-inhibitory properties of 2-pyridyl-thioacteamide (CMN131). Removal of the thioamide group was considered to be the most likely solution to the toxicity of CMN131, which prompted the preparation of sulfur-containing heterocycles, as well as imidazo-line- and benzimidazole-linked sulfides. However, it was the corresponding S-oxide analogs of the latter compounds that proved the more potent; it thus became clear that the mechanism of action of timoprazole was distinct from that of H2-receptor antagonism. Timoprazole was subsequently followed by the more potent derivatives picoprazole in 1976 and omeprazole in 1979 (119). The three main structural features of omeprazole (i.e., the substituted pyridine ring; the substituted benzimidazole; and the methylsulfinyl linking group, by which these two ring systems are attached to one another) are essential, either in generating the active form from its inactive precursor or in binding irreversibly with the H+/K+-ATPase enzyme. For this reason, compounds inhibiting acid secretion by this mechanism and lacking one or more of these features are scarce. Moreover, for irreversible proton-pump inhibitors to achieve selective biological activity, their mechanism of action demands that they have relatively high chemical stability around neutral pH, but be readily activated at low pH. This chemical profile also influences attendant issues such as synthesis, formulation, and storage, and because biological activity of this class of compounds often correlates with chemical lability, not all compounds, which achieve potent inhibitory behavior in vitro, are viable drug candidates because they are inherently too chemically unstable.

The gastric proton-pump inhibitors currently available (Fig. 3.10) all retain the same key chemical features present in omeprazole, indicating that the structural requirements to achieve irreversible inhibition of the gastric ATPase enzyme are precisely defined. The clinical properties of this latter group of drugs is discussed more fully in section 9.6, whereas the remainder of this section focuses on other candidates currently or previously under de

Proton Pump Inhibitor Moa With Figure
Figure 3.7. Conversion of omeprazole to its active state within an acidic environment. Oral administration of enterically coated omeprazole ensures maximal activation occurs within the parietal cell.

velopment. As discussed above, the potency of irreversible proton-pump inhibitors is a time-and pH-dependent property, making comparison of their in vitro potency difficult, given the wide range of assay conditions employed

(Table 3.5 and Fig. 3.9). Where possible, their potency relative to omeprazole, measured under the same assay conditions, is indicated. However, notwithstanding differences in the stimulant used, comparison of their in vivo

Figure 3.8. Acid-catalyzed activation of omeprazole to form the active pyridinium sulfenamide or sulfenic acid. Only one isomer of intermediates (a) and (b) is shown.

effective, most likely because of their greater chemical stability. Although many of the compounds lack substituents on the benzimid-azole ring, the presence of electron-donating groups at the 5-position, such as methoxy (omeprazole),SKF 95601, OPC-22575 (129), S-337 (128), pyrrol-1-yl (IY-81149) (130), and difluoromethoxy (pantoprazole),also provided an optimum balance of chemical stability and reactivity. In fact, the presence of electron-withdrawing substituents in this position, such as nitro, methylsulfinyl, and trifluor-methyl, increases the basicity of the benzimid-ring to the point where the behavior of these compounds is dominated by activation at neutral pH, resultingin compounds having poor chemical stability and limited practical value (131).

In contrast, increasing the nucleophilic character of the pyridine ring, by the incorporation of electron-donating substituents, en-

Saviprazole

Table 3.5 Biologû

Structure

In Vitro

IC50}MM(IC50f julM, omeprazole)

In Vivo Inhibition of Gastric Acid Secretion in Rat by Enteral Administration, ED,„ mg kg"1 (ED50, mgkg-1, omeprazole)

Ref.

Disuprazole

Disuprazole (Upjohn)

Disuprazole (Upjohn)

Disuprazole

TY-11345 (Tao Eiyo KK)

TY-11345 (Tao Eiyo KK)

Disuprazole

SKF 95601 (SmithKline & French)

1.14d

SKF 95601 (SmithKline & French)

HgCO

HgCO

Main Structure Proton Pump Inhibitor

Tenatoprazole (Mitsubishi-Tokyo Pharm. Inc.)

Tgfbr1 Inhibitor Sar

H3CO

OCH2CF2CF2CF3 Saviprazole (Hoechst AG)

OCH2CF2CF2CF3 Saviprazole (Hoechst AG)

H3CO

OPC-22575 (Otsuka Phsirm. Co. Ltd.)
Disuprazole
H,C

OCH,

l.Sb 127

Structure

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