Urea and amide-based inhibitors of the juvenile hormone epoxide hydrolase of the tobacco hornworm (Manduca sexta: Sphingidae)

Tonya F. Severson, Marvin H. Goodrow, Christophe Morisseau, Deanna L. Dowdy, Bruce D. Hammock

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

A new class of inhibitors of juvenile hormone epoxide hydrolase (JHEH) of Manduca sexta and further in vitro characterization of the enzyme are reported. The compounds are based on urea and amide pharmacophores that were previously demonstrated as effective inhibitors of mammalian soluble and microsomal epoxide hydrolases. The best inhibitors against JHEH activity so far within this class are N-[(Z)-9-octadecenyl]-N′-propylurea and N-hexadecyl-N′-propylurea, which inhibited hydrolysis of a surrogate substrate (t-DPPO) with an IC50 around 90 nM. The importance of substitution number and type was investigated and results indicated that N, N′-disubstitution with asymmetric alkyl groups was favored. Potencies of pharmacophores decreased as follows: amide>urea>carbamate>carbodiimide>thiourea and thiocarbamate for N, N′-disubstituted compounds with symmetric substituents, and urea>amide>carbamate for compounds with asymmetric N, N′-substituents. JHEH hydrolyzes t-DPPO with a Km of 65.6 μM and a Vmax of 59 nmol main-1 mg-1 and has a substantially lower Km of 3.6 μM and higher Vmax of 322 nmol min-1 mg-1 for JH III. Although none of these compounds were potent inhibitors of hydrolysis of JH III by JHEH, they are the first leads toward inhibitors of JHEH that are not potentially subject to metabolism through epoxide degradation.

Original languageEnglish (US)
Pages (from-to)1741-1756
Number of pages16
JournalInsect Biochemistry and Molecular Biology
Volume32
Issue number12
DOIs
StatePublished - Dec 1 2002

Keywords

  • Amide
  • Carbamates
  • Inhibitors
  • Juvenile hormone epoxide hydrolase
  • Kinetics
  • Manduca sexta
  • Metabolism
  • Structure activity relationships (SAR)
  • Urea

ASJC Scopus subject areas

  • Insect Science
  • Biochemistry

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