Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors

Ashok Rakhit, Steve K. Kuwahara, David R. Jones, Victor F. Soliman, Alvin N. Kotake, Thomas D. Oglesby, Jan W.F. Wasley, Spencer L. Tripp, Frank L. Douglas

Research output: Contribution to journalArticle

3 Scopus citations


The o-naphthoquinone derivative, CGS 8515 (I), is a potent inhibitor (IC50, 0.1 µM) of 5-lipoxygenase, but its therapeutic potential is compromised by a short plasma half-life (22 min) and extremely poor oral bioavailability (<2%). Poor biopharmaceutical properties of CGS 8515 were attributed to poor aqueous solubility and rapid in vivo hydrolysis of its methyl ester function to an inactive metabolite (IC50, 100 µM). An active amide analogue (II) was synthesized to prevent rapid hydrolysis. While analogue II appeared to be stable in vivo, its plasma half-life was also short (10 min), possibly because of rapid tissue distribution rather than metabolic elimination. Therefore, three potent analogues with increased aqueous solubilities were synthesized and compared with respect to their pharmacokinetic properties. The analogue with the highest aqueous solubility (V) demonstrated a plasma concentration vs time profile with the largest area under the curve (AUC) and the smallest distribution (α) phase of all the analogues studied. The percentage AUC of the terminal phase (β) for three analogs paralleled their aqueous solubilities. The oral bioavailability of V was improved to 27%, compared to 2% for the parent compound, CGS 8515.

Original languageEnglish (US)
Pages (from-to)1071-1076
Number of pages6
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Issue number10
StatePublished - Oct 1990


  • 5-lipoxygenase inhibitor
  • drug design
  • o-quinone analogues
  • pharmacokinetic screening

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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    Rakhit, A., Kuwahara, S. K., Jones, D. R., Soliman, V. F., Kotake, A. N., Oglesby, T. D., Wasley, J. W. F., Tripp, S. L., & Douglas, F. L. (1990). Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors. Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists, 7(10), 1071-1076.