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.
Subject(s)
Alanine/analogs & derivatives , Prodrugs/chemical synthesis , Thiorphan/analogs & derivatives , Alanine/chemical synthesis , Alanine/isolation & purification , Chemistry, Pharmaceutical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/isolation & purification , Humans , Prodrugs/isolation & purification , Stereoisomerism , Thiorphan/chemical synthesis , Thiorphan/isolation & purificationABSTRACT
The design of 1,3-dacylaminopropan-2-ols as CNS-directed carrier groups is based on their resemblance to endogenous lipids and the properties of pseudotriglyceride esters to facilitate the brain penetration of therapeutic agents. 2-[S-acetylthiorphan]-1,3-diacylaminopropan-2-ols, differing from the nature of 1,3-acyl chains, were synthesized and evaluated in vivo using the hot-plate jump test. The compounds exhibited naloxone reversible analgesic properties. The effects were superior to those of parent compounds thiorphan and S-acetylthiorphan. The palmitoyl derivative showed also activity at 0.8 mmol/kg after oral administration. Like acetorphan, a thiorphan prodrug, these compounds were poor substrates for brain enkephalinase, suggesting the release of the pharmacological active inhibitor at the site of action in the brain.
Subject(s)
Analgesics/chemical synthesis , Neprilysin/antagonists & inhibitors , Thiorphan/analogs & derivatives , Thiorphan/chemical synthesis , Administration, Oral , Analgesics/administration & dosage , Analgesics/pharmacology , Animals , Blood-Brain Barrier/drug effects , Brain/enzymology , Brain/metabolism , Drug Carriers , Injections, Intravenous , Male , Mice , Naloxone/pharmacology , Pain Measurement/drug effects , Thiorphan/pharmacologyABSTRACT
As hydrolysis in serum of acetorphan to acetylthiorphan (N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]glycine) has been evidenced, both the neutral endopeptidase inhibition in vitro by acetylthiorphan and analgesic potency of acetylthiorphan after intravenous administration to mice in two analgesic models, the hot-plate and the tail-flick tests, were compared with those of thiorphan and acetorphan. Acetylthiorphan showed a decreased degree of neutral endopeptidase inhibition (IC50 = 316 +/- 38 nM) compared to thiorphan (IC50 = 1.8 +/- 0.2 nM). After intravenous administration followed by the hot-plate jump latency test, acetylthiorphan elicited a degree of analgesia equivalent to that with acetorphan but longer lasting. Like acetorphan and thiorphan, acetylthiorphan was devoid of analgesic activity in the tail-flick test. The results indicated that S-acetylation of the thiol function in acetylthiorphan ensures sufficient lipophilicity to permit crossing of the blood-brain barrier and that acetylthiorphan acts via a prodrug mechanism.