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 Citations (Scopus)

Abstract

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
Volume7
Issue number10
DOIs
StatePublished - 1990

Fingerprint

Lipoxygenase Inhibitors
Pharmacokinetics
Solubility
Screening
Plasmas
Biological Availability
Inhibitory Concentration 50
Area Under Curve
Half-Life
Hydrolysis
Arachidonate 5-Lipoxygenase
Tissue Distribution
Metabolites
Amides
Esters
Tissue
Derivatives
1,2-naphthoquinone
methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate
Therapeutics

Keywords

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

ASJC Scopus subject areas

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

Cite this

Rakhit, A., Kuwahara, S. K., Jones, D. R., Soliman, V. F., Kotake, A. N., Oglesby, T. D., ... Douglas, F. L. (1990). Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors. Pharmaceutical Research, 7(10), 1071-1076. https://doi.org/10.1023/A:1015903519637

Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors. / Rakhit, Ashok; Kuwahara, Steve K.; Jones, David R.; Soliman, Victor F.; Kotake, Alvin N.; Oglesby, Thomas D.; Wasley, Jan W F; Tripp, Spencer L.; Douglas, Frank L.

In: Pharmaceutical Research, Vol. 7, No. 10, 1990, p. 1071-1076.

Research output: Contribution to journalArticle

Rakhit, A, Kuwahara, SK, Jones, DR, Soliman, VF, Kotake, AN, Oglesby, TD, Wasley, JWF, Tripp, SL & Douglas, FL 1990, 'Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors', Pharmaceutical Research, vol. 7, no. 10, pp. 1071-1076. https://doi.org/10.1023/A:1015903519637
Rakhit A, Kuwahara SK, Jones DR, Soliman VF, Kotake AN, Oglesby TD et al. Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors. Pharmaceutical Research. 1990;7(10):1071-1076. https://doi.org/10.1023/A:1015903519637
Rakhit, Ashok ; Kuwahara, Steve K. ; Jones, David R. ; Soliman, Victor F. ; Kotake, Alvin N. ; Oglesby, Thomas D. ; Wasley, Jan W F ; Tripp, Spencer L. ; Douglas, Frank L. / Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors. In: Pharmaceutical Research. 1990 ; Vol. 7, No. 10. pp. 1071-1076.
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