Chapter 5. Esomeprazole in the Framework of Proton-Pump Inhibitor Development

  1. Dr. János Fischer2,
  2. Prof. Dr. C. Robin Ganellin3
  1. Per Lindberg,
  2. Enar Carlsson

Published Online: 22 MAY 2006

DOI: 10.1002/3527608001.ch5

Book Title

Analogue-based Drug Discovery

Analogue-based Drug Discovery

Additional Information

How to Cite

Lindberg, P. and Carlsson, E. (2006) Esomeprazole in the Framework of Proton-Pump Inhibitor Development, in Analogue-based Drug Discovery (eds J. Fischer and C. R. Ganellin), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG. doi: 10.1002/3527608001.ch5

Editor Information

  1. 2

    Gedeon Richter Ltd., P.O. Box 27, H-1475 Budapest 10, Hungary

  2. 3

    University College London, Department of Chemistry, 20 Gordon Street, London WC1H OAJ, UK

Author Information

  1. AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden

Publication History

  1. Published Online: 22 MAY 2006
  2. Published Print: 20 JAN 2006

ISBN Information

Print ISBN: 9783527312573

Online ISBN: 9783527608003

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CHAPTER TOOLS

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Keywords:

  • analogue-based drug discovery;
  • esomeprazole;
  • proton-pump inhibitor development;
  • omeprazole;
  • acid-related disorders;
  • Losec®;
  • research at Hässle;
  • pH-stability profile;
  • omeprazole isomers

Summary

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

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