2-[(2-Pyridylmethyl)sulfinyl]-1H-thieno[3,4-d]imidazoles. A novel class of gastric H+/K+-ATPase inhibitors

Abstract

2-[(2-Pyridylmethyl)sulfinyl]thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The [3,4-d] isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo. Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno[3,4-d]imidazole lead to highly active compounds with a favorable chemical stability. Various substitution patterns in the thieno[3,4-d]imidazole moiety result in lower biological activity. The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation. Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K(+)-ATPase blocker introduced on the market.

Total synthesis of 5-hydroxyomeprazole

“…Subsequent hydrolysis of 25 with NaOH in aqueous methanol overnight furnished 26 in excellent yield (90%). Since Omeprazole (1) and its analogues are sensitive to acidic conditions, 15 oxidation of sulfide 26 with m-CPBA was performed in DCM and aqueous NaHCO 3 solution under argon following the procedure reported by Kuhler.…”

Synthesis of Thieno[2,3-d]imidazoles by Copper-Catalyzed Amidine Cyclization

“…2 Preclinical studies of thieno[2, 3-d]imidazole derivatives have shown activity in the treatment of osteoarthritis, 3 hepatitis C 4 and gastric acid regulation. 5 Figure 1 Biologically active thieno[2, 3-d]imidazoles…”

Nicotinamide Derivatives as a New Class of Gastric H+/K+-ATPase Inhibitors. 1. Synthesis and Structure−Activity Relationships of N-Substituted 2-(Benzhydryl- and benzylsulfinyl)nicotinamides

“…However, there is another possibility of this successive reaction taking place not only within the acid compartment of the parietal cells but also at weakly acidic pH conditions outside the parietal cells . All known irreversible H + /K + -ATPase inhibitors do not exhibit activity by the mechanism described above, but they are structurally similar to the PSBs , and their analogues. − On the basis of the mechanism of pH-dependent inhibition as observed in the PSBs, we aimed to find out potent and more selective inhibitors of H + /K + -ATPase in vivo, which have a different structure from PSBs.

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“…3 All known irreversible H + / K + -ATPase inhibitors do not exhibit activity by the mechanism described above, but they are structurally similar to the PSBs 5,6 and their analogues. [7][8][9][10][11][12][13][14] On the basis of the mechanism of pH-dependent inhibition as observed in the PSBs, we aimed to find out potent and more selective inhibitors of H + /K + -ATPase in vivo, which have a different structure from PSBs.…”