Synthesis, ex Vivo and in Vitro Hydrolysis Study of an Indoline Derivative Designed as an Anti-Inflammatory with Reduced Gastric Ulceration Properties

Abstract

The compound 1-(2,6-dichlorophenyl)indolin-2-one (1), planned as a pro-drug of diclofenac (2), was easily synthesized in 94% yield by an intramolecular reaction in the presence of coupling agent (i.e., EDC). Compound 1 showed anti-inflammatory and analgesic activity without gastro-ulcerogenic effects. The chemical and enzymatic hydrolysis profile of the lactam derivative 1 does not indicate conversion to diclofenac (2). This compound is a new non-ulcerogenic prototype for treatment of chronic inflammatory diseases.

Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

“…All results were statistically significant when compared to the aqueous solution of sodium carboxymethylcellulose (0.5% w / v ) used as the control (not shown). At 300 μmol/kg, the anti-inflammatory activity was the same observed in our previous at 100 μmol/kg [16]. …”

“…Preliminar in vivo pharmacokinetic study demonstrated bioconversion of diclofenac prodrug to parental drug after administration, despite in vitro chemical and plasmatic studies have not demonstrated this conversion [16]. These results allow us to corroborate the success of our molecular modification strategy.…”

“…We have previously described that masking acid function of diclofenac into lactam derivatives could provide compounds with anti-inflammatory activity with the same nonulcerogenic properties. However, previous in vitro chemical and plasmatic studies have not demonstrated the conversion of prodrug to diclofenac [16,23]. …”

“…We have observed that the number of ulcers at 300 μmol/kg was higher than at 100 μmol/kg. However, in both cases, the diclofenac prodrug (1) demonstrated to be safer than diclofenac (2) [16]. …”

“…This approach could be useful to modify known NSAIDs in order to identify compounds with reduced gastrointestinal effects and different pharmacokinetic and pharmacodynamic profiles [13–15]. Using the prodrug approach, we have shown that lactam derivative (1) demonstrated anti-inflammatory and analgesic activity similar to the parental drug (Figure 1) [16]. …”