Strategies for Access to Enantiomerically Pure Ecadotril, Dexecadotril and Fasidotril: A Review

Authors: Monteil T.; Danvy D.; Sihel M.; Leroux R.; Plaquevent J-C.

Source: Mini Reviews in Medicinal Chemistry, Volume 2, Number 3, June 2002 , pp. 209-217(9)

Publisher: Bentham Science Publishers

Abstract:

Ecadotril and dexecadotril are powerful and selective inhibitors of neprilysin (NEP, EC 3.4.24.11) and are being developed as therapeutic agents, since they behave as prodrugs of the enantiomers of thiorphan. They exhibit different pharmaceutical profiles (intestinal antisecretatory action for the (R) enantiomer, i.e. dexecadotril, and cardiovascular activity for the (S) enantiomer, i.e. ecadotril). Fasidotril is a related compound which has special interest as an equipotent dual inhibitor of NEP and ACE (EC 3.4.15.1). This behavior confers on fasidotril powerful pharmaceutical properties in the cardiovascular field. This review deals with various synthetic approaches, either published or patented, for access to the enantiomerically pure or highly enriched forms of these drugs. Thus, different methods have been studied, which are taken from different methodologies of resolution procedures and asymmetric synthesis, namely :

i- Synthesis from a chiron from the chiral pool

ii- Chemical resolution of racemic precursors

iii- Enzymatic resolution and desymmetrization of meso starting materials

iv- Asymmetric synthesis, including enantioselective catalytic hydrogenation, alkaloid catalyzed asymmetric Michael additions, and diastereoselective alkylation of a chiral derivative.

Some of these methods are used in industrial processes leading to the indicated compounds.

Keywords: ecadotril; dexecadotril; fasidotril; neprilysin inhibitor

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389557023406133

Publication date: 2002-06-01

• The aim of Mini-Reviews in Medicinal Chemistry is to publish short reviews on the important recent developments in medicinal chemistry and allied disciplines.
  
  The scope of Mini-Reviews in Medicinal Chemistry will cover all areas of medicinal chemistry including developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, drug targets, and natural product research and structure-activity relationship studies.
  
  Mini-Reviews in Medicinal Chemistry is an essential journal for every medicinal and pharmaceutical chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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• In this Subject: Chemistry (General) ,  Pharmacology
• By this author: Monteil T. ;  Danvy D. ;  Sihel M. ;  Leroux R. ;  Plaquevent J-C.

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