Hydrolysis of oleylanilide in the rat

Abstract

The fate of oleylanilide, administered as a single intragastric dose in rape oil, has been studied in Porton Wistar rats. Following a dose of oleyl[U-14C]anilide approximately 60% of the label was recovered in the faeces over a 3 day period, and identified principally as unchanged anilide. Most of the remainder of the dose was recovered in urine as hydrophilic metabolites. p-hydroxyacetanilide, which is a major metabolite of aniline in the rat was identified in the hydrolysed samples of urine from anilide treated rats. Following administration of [9,10(n)-3H]oleyl[U-14C]-anilide to rats which had been fitted with a cannula in the thoracic lymph duct the [3H] label which was absorbed was recovered principally in triglycerides showing that extensive hydrolysis of the anilide occurs prior to or during uptake from the gut. Oleylanilide was identified in lymph by gas chromatography but amounted to less than 6% of the dose.

Discovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical Effect

“…While the discovery of stilbene 10a represented a significant simplification of the chemotype and an advance for the program, the potential of this chemotype as a vehicle for drug discovery was compromised by two liabilities inherent to the structure. The potential for the olefin to undergo cis / trans isomerization was viewed as problematic, while the anilide moieties were of greater concern because of the risk for the release of a potentially toxic aniline moiety in vivo should the molecule be recognized by amidases or be subject to hydrolytic decomposition in the gut . An additional and more substantial complication that emerged shortly after the discovery of 10a was associated with the development of a replicon system that allowed evaluation of inhibitory activity toward the GT-1a subtype.…”

2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph

“…While the high level of antiviral potency associated with stilbene 90 was attractive, this compound presented three problems that were considered to be of significance in further optimization. From the perspective of chemical structure, the stilbene olefin was subject to configurational instability via cis–trans isomerism, observed in studies with analogues of 90 , while the embedded aniline moiety was of concern because of the potential for release in vivo by protease- or esterase-mediated cleavage of the proline amide bond. , Anilines are potentially mutagenic and genotoxic after metabolic activation, arousing considerable anxiety around this potential safety issue . While it was anticipated that these issues could be addressed by a series of structure–activity studies, the discovery of 89 and 90 coincided with the development of a GT-1a replicon where both compounds were determined to be essentially inactive, with EC 50 values of >10 μM.…”