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Abstract

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.

A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

“…In NMRI mice i.v. acetyl-thiorphan and thiorphan were also effective in this model, although thiorphan less than the more lipophilic acetyl-thiorphan and racecadotril (Lambert et al, 1993, 1995). I.v.…”

“…Inhibition of purified NEP activity from mouse brain yielded affinity estimates ( K i values) of 6.1 and 4500 nM for thiorphan and racecadotril, respectively; however, when racecadotril was pre-incubated with rat brain membranes for 15 min, an apparent K i value of 8.6 nM was observed, probably reflecting rapid in vitro conversion to thiorphan (Lecomte et al, 1986). A similar study reported an IC 50 of 1.8 nM for thiorphan with racecadotril being 1000 times less potent and acetyl-thiorphan having a value of 316 nM (Lambert et al, 1993, 1995). For in vitro inhibition of rat kidney NEP an IC 50 of 5.4 nM was reported (Fink et al, 1995), apparently reflecting in vitro conversion to thiorphan as shown before in rat brain (Lecomte et al, 1986).…”

“…administration (Roques et al, 1980) and with i.v. administration in Swiss albino (Lecomte et al, 1986; Costentin et al, 1998), NMRI (Lambert et al, 1993, 1995) and DBA/2J mice but not C57BL/6J mice (Michael-Titus et al, 1989). Interestingly, in the latter study racecadotril increased locomotion in both strains, indicating that the difference in analgesic effect does not reflect a pharmacokinetic strain difference.…”

Progress in Drug Delivery to the Central Nervous System by the Prodrug Approach

“…It was then demonstrated by Fournie-Zaluski et al [ 21 ] that the benzyl ester of acetorphan is rapidly hydrolyzed in serum and so the metabolite S -acetyltiorphan accounts for the BBB penetration. Taking advantage of this information Lambert et al [ 22 ] have synthesized a series of amide pseudotriglycerides of S -acetylthiorphan ( 5 , Figure 2 ) in which the ester bonds in positions 1 and 3 of the glyceride have been replaced by amide bonds in order to increase metabolic stability. These compounds were shown to exhibit analgesic proprieties superior to those of thiorphan and S -acetylthiorphan, suggesting that they were acting as prodrugs.…”

Synthesis and In Vitro Skin Permeation of Naproxen Conjugates with α- Alkylamino Acids

“…Lipidic prodrugs and conjugates have been described using various chemical strategies, from glycerides to fatty acid derivatives [2,3].…”