Therapeutic effects of isothiocyanate prodrugs on rheumatoid arthritis

Bioorg Med Chem Lett. 2018 Feb 15;28(4):737-741. doi: 10.1016/j.bmcl.2018.01.009. Epub 2018 Jan 8.

Abstract

Isothiocyanates 7a and 7b have poor stability and aqueous solubility. To address these problems, prodrugs 8a and 8b were synthesized. Prodrugs 8a and 8b were stable in HEPES buffer at pH 4.4, but released the active compounds 7a and 7b in HEPES buffer at pH 7.4 and in mouse plasma, respectively. Compound 8a and especially compound 8b showed anti-inflammatory effects. Compound 8b demonstrated significant efficacy in animal models of traumatic inflammation, acute inflammation and rheumatoid arthritis. Compound 8b also did not cause appreciable toxicity in mice after 5 weeks at a daily dose of 200 mg/kg.

Keywords: Active drug; Acute inflammation; Isothiocyanate prodrug; Rheumatoid arthritis; Traumatic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Arthritis, Rheumatoid / drug therapy*
  • Body Weight / drug effects
  • Half-Life
  • Isothiocyanates / chemical synthesis
  • Isothiocyanates / pharmacokinetics
  • Isothiocyanates / therapeutic use*
  • Isothiocyanates / toxicity
  • Mice
  • Neutrophils / drug effects
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use*
  • Prodrugs / toxicity
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Zebrafish

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Isothiocyanates
  • Prodrugs