Esomeprazole in the Framework of Proton‐Pump Inhibitor Development

This chapter contains sections titled: Towards Omeprazole: The First Proton-Pump Inhibitor The Treatment of Acid-Related Disorders Before Losec® Pioneer Research at Hässle during the 1960s and 1970s Toxicological Challenges Discovery of H+, K+-ATPase: The Gastric Proton Pump Analogue Optimization The Development of Omeprazole Further Toxicological Challenges and the Halt of the Clinical Program Resumption of Clinical Studies Omeprazole Reaches the Market and Supersedes H2-Receptor Antagonists The Unique Action of Omeprazole Inhibition of the Final Step Omeprazole Binds Strongly to the H+, K+-ATPase Inhibition of Acid Secretion and H+, K+-ATPase Activity Omeprazole Concentrates and Transforms in Acid Disulfide Enzyme–Inhibitor Complex on the Luminal Side Short Half-Life in Plasma and Long Half-Life for Enzyme–Inhibitor Complex Mechanism at the Molecular Level The “Targeted Prodrug” Omeprazole means a Highly Specific Action pH-Stability Profile Omeprazole Analogues Synthesized by Other Companies Omeprazole: A Need for Improvement? The Omeprazole Follow-Up Program No Good Alternative to the Omeprazole Structural Template Chemical Approach Synthesis and Screening Isomers Seemed Unattractive Isomer Pharmacokinetics and Pharmacodynamics in Animals The Key Experiment in Man Production of Esomeprazole (Mg Salt) Omeprazole Isomers: Differences in Clearance and Metabolic Pattern Summary