Strategies for access to enantiomerically pure ecadotril, dexecadotril and fasidotril: a review.
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.
Monteil
Thierry
T
UMR 6014 de l'IRCOF, Faculté des Sciences, Université de Rouen, Rue Tesnière, Mont-Saint-Aignan, Cedex, F-76821, France.
Danvy
Denis
D
Sihel
Miryam
M
Leroux
Richard
R
Plaquevent
Jean-Christophe
JC
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification; D002626:Chemistry, Pharmaceutical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000302:isolation & purification; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000302:isolation & purification; D013237:Stereoisomerism; D015244:Thiorphan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification
D004791:Enzyme Inhibitors; D011355:Prodrugs; C469873:dexecadotril; C049331:racecadotril; D015244:Thiorphan; C097293:aladotril; D000409:Alanine